Compositions and methods of treatment of cancer

ABSTRACT

This invention generally relates to compositions and methods for cancer treatment and, in particular, to compositions able to interact (e.g., bind to) with MUC1 growth factor receptor or its ligands, and methods for treating the same. The invention also relates to assays or use of such compositions for the treatment of patients susceptible to or exhibiting symptoms characteristic of cancer or tumorigenesis. Other compositions of the present invention useful for the treatment or prevention of cancer or tumorigenesis include homologs, analogs, derivatives, enantiomers or functional equivalents. The present compositions can also be packaged in kits in some cases.

RELATED APPLICATIONS

[0001] This non-provisional application claims the benefit under Title35, U.S.C. §119(e) of co-pending U.S. Provisional Patent Application No.60/317,302, filed Sep. 5, 2001, entitled “Compositions and Methods ofTreatment of Cancer,” by C. Bamdad, et al.; and U.S. Provisional PatentApplication No. 60/376,732, filed May 1, 2002, entitled “Compositionsand Methods of Treatment of Cancer,” by C. Bamdad, et al. Theseapplications are incorporated herein by reference.

FIELD OF THE INVENTION

[0002] This invention generally relates to compositions and methods forcancer treatment and, in particular, to compositions able to interactwith MUC1 Growth Factor Receptor or its ligands, and methods fortreating the same.

DESCRIPTION OF THE RELATED ART

[0003] Many biomolecular interactions that promote tumorigenesis involvecell surface proteins that can mediate intra- or intercellularsignaling. The tumor markers generally are proteins on the surface of acell that may become exclusively expressed, overexpressed, or show analtered expression pattern, as a result of transformation of the cell toa neoplastic state. The surface concentration of certain tumor markershas been correlated with the progression of cancer. For example, theinteraction between the integrin cell surface receptor alpha-v-beta-3(α_(v)β₃) and the cell adhesion molecule vitronectin has been implicatedin angiogenesis, and the increased concentration of alpha-v-beta-3 onmelanoma cells has been correlated with poor prognosis.

[0004] Cell surface receptors that have been linked to cancer make up animportant class of therapeutic targets. Many pharmaceutical companiesare actively involved in screening drug libraries for compounds thatbind to and block these cell surface receptors. For example, animportant drug used to treat breast cancer is Herceptin. This drug isbelieved to be able to bind to and block HER2/neu, which is a cellsurface receptor overexpressed in about 30% of breast tumors.

[0005] Another cell surface receptor, MUC1, is interesting since it isbelieved to be aberrantly expressed in many human tumors, includingabout 80% or 90% of breast tumors, and in a significant percentage ofother human tumors, such as prostate, lung, ovarian, colorectal, andperhaps brain cancer. On healthy secretory epithelium, MUC1 is believedto be clustered at the apical border of the epithelium and is notsignificantly expressed in other portions of the cell. However, in tumorcells, the receptor is generally overexpressed homogeneously over themajority of the cell surface, rather than primarily at the apicalborder. It is also believed that women with breast cancer may haveelevated levels of shed MUC1 receptor in their blood. Levels of shedMUC1 receptor in blood serum thus can be measured to track breast cancerin breast cancer patients, for example, to determine recurrence of thedisease. However, the method is generally too variable and insensitiveto be used as a diagnostic tool.

[0006] Until now, the mechanistic link between the MUC1 receptor andtumorigenesis has not been well understood. Attempts to correlate thenumber of repeat units (which can vary from person to person) with thesusceptibility to cancer have generally failed. Investigations of apossible connection between glycosylation of the MUC1 receptor andcancer have produced conflicting and inconsistent results. Importantly,until now, functional ligands for the extracellular portion of the MUC1receptor have not been identified.

[0007] Absent an understanding of the biological mechanism of action ofthe MUC1 receptor, and how the MUC1 receptor is able to triggertumorigenesis, it has not been possible to design or identifytherapeutics that interfere with the disease-associated function of thisreceptor. Indeed, there is no drug currently in use or, to ourknowledge, in clinical trials, that is known to target the MUC1receptor.

SUMMARY OF THE INVENTION

[0008] This invention generally relates to compositions that are able toinhibit interactions involving the MUC1 Growth Factor Receptor or itsligands, and methods for treating patients displaying symptoms of, orsusceptible to MUC1-associated cancers. The subject matter of thisapplication involves, in some cases, interrelated products, alternativesolutions to a particular problem, and/or a plurality of different usesof a single system or article.

[0009] Several methods are disclosed herein of administering to asubject a composition for prevention or treatment of a particularcondition. It is to be understood that in each such aspect of theinvention, the invention specifically includes the composition for usein the treatment or prevention of that particular condition, as well asuse of the composition for the manufacture of a medicament for thetreatment or prevention of that particular condition. In some aspects ofthe invention, the invention also includes a pharmaceutically acceptablecarrier.

[0010] The present invention includes methods of treatment of selectedgroups of patients. It is to be understood that all compositionsdescribed herein are useful for each described method.

[0011] Also included in the present invention is a combinatorialapproach in which structural features identified as characteristic ofcompositions effective for treatment at various disease stages are usedas the basis for combinatorial synthesis of a wide variety of structuralhomologs, analogs, derivatives, enantiomers and functionally equivalentcompositions thereof, for identification of a wide variety ofcompositions useful for treatment MUC1-associated cancers. Thus, in oneembodiment, the invention involves providing any one of compositions1-51, performing a combinatorial synthesis resulting in a plurality ofcompositions. Then, one can perform an assay involving the plurality ofthe compositions to determine their effectiveness in cancer treatment,specifically, treatment of cancers disclosed herein. Compositions 1-51also can be altered using medicinal chemistry techniques.

[0012] Another aspect of the invention provides a pharmaceuticalpreparation comprising a composition comprising any of the compositions1-51, and a pharmaceutically active carrier. In one embodiment, thecomposition comprises homologs, analogs, derivatives, enantiomers andfunctionally equivalent compositions thereof of compositions 1-51. Inall structures herein, atom locations, if unlabeled, are carbon withappropriate hydrogen(s).

[0013] The invention also provides a method involving promoting theprevention or treatment of MUC1-associated cancer via administration ofany one of the compositions of the present invention and homologs,analogs, derivatives, enantiomers and functionally equivalentcompositions thereof.

[0014] In another aspect the invention provides a kit including any oneof the compositions of the present invention and homologs, analogs,derivatives, enantiomers and functionally equivalent compositionsthereof; and instructions for use of these compositions for treatment ofcancer characterized by aberrant expression of MUC1.

[0015] In one aspect, the invention includes a composition. In one setof embodiments, the composition has a structure:

[0016] where A¹, A², A³, A⁴, Y¹, Y², and Y³ can each be independentlyselected from the group consisting of H and a halogen, G can be a grouphaving one carbon only, optionally in combination with other atoms (e.g.methoxy), and R², R³ and R⁴ each independently comprise at least oneatom. In one embodiment, each of A¹, A², A³, A⁴, Y¹, Y², and Y³ can beH, G can be methyl or methoxy, R² can be methyl or ethyl, R³ can be acyclic aromatic or an alkyl of from 2-6 carbon atoms, and R⁴ can be-NHR5, where R5 can be a cyclic aromatic, optionally substituted.

[0017] In another set of embodiments, the composition has a structure:

[0018] where A¹, A², A³ and A⁴ can each be independently selected fromthe group consisting of H, methyl, or a halogen, Z comprises at leastthree carbon atoms, and R², R³ and R⁴ each independently comprise atleast one atom. —O—Z, as depicted, can be bound to any of the availableverticies of the ring from which it emanates. This interpretationapplies to other, similarly-depicted structures herein. In oneembodiment, each of A¹, A², A³, A⁴ can be H, methyl, or a halogen, R¹comprises a cyclic aromatic, R² can be methyl or ethyl, R³ and R⁴ eachincludes a cyclic aromatic.

[0019] In another set of embodiments, the composition has a structure:

[0020] where A¹, A², A³ and A⁴ can each be independently selected fromthe group consisting of H, methyl, or a halogen, R¹, R², and R⁴ eachindependently comprise at least one atom, and R³ comprises a branchedalkyl group or at least 6 carbon atoms. In one embodiment, A¹, A², A³,A⁴ can each be H, R¹ can be an aromatic group, R² can be methyl orethyl, R³ includes a cyclic aromatic, and R⁴ includes a cyclic aromaticor two fused rings or can be an alkyl group of from 1-4 carbon atomssubstituted with 2 halogens.

[0021] In another set of embodiments, the composition has a structure:

[0022] where A¹, A², A³, A⁴, Y¹, and Y² can each be independentlyselected from the group consisting of H, methyl, or a halogen, R¹, R²,and R³ each independently comprise at least one atom, Q comprises achemical bond or an alkyl group, and X comprises a halogen. In oneembodiment, A¹, A², A³, A⁴ can each be H, R¹ can be an aromatic group,R² can be methyl or ethyl, R³ can be an alkyl group, branched in oneembodiment, Q can be a chemical bond, X can be chlorine, Y¹ can bechlorine, and Y¹ can be hydrogen.

[0023] In another set of embodiments, the composition has a structure:

[0024] where A¹, A², A³ and A⁴ can each be independently selected fromthe group consisting of H, methyl, or a halogen, R¹, R², and R³ eachindependently comprise at least one atom, Q comprises a chemical bond oran alkyl group, and E comprises at least 2 cyclic groups in a branchedconfiguration. In one embodiment, each of A¹, A², A³, A⁴ can be H,methyl, or a halogen, R¹ can be an aromatic group, R² can be methyl orethyl, R³ can be an alkyl group or cyclic structure, Q can be a chemicalbond, E includes at least two aromatic groups, and in one embodiment canbe diphenyl methyl.

[0025] In another set of embodiments, the composition has a structure:

[0026] where A¹, A², A³ and A⁴ can each be independently selected fromthe group consisting of H, methyl, or a halogen, R², R³, R¹¹, R¹², R¹³,R¹⁴, and R¹⁵ each independently comprise at least one atom, Q comprisesa chemical bond or an alkyl group, and at least two of L¹, L², L³, L⁴,and L⁵ can be interconnected via a saturated moiety. In one embodiment,each of A¹, A², A³, A⁴ can be H, methyl, or a halogen, R² can be methylor ethyl, each of R¹¹, R¹², R¹⁴, R¹⁵ can be H, R¹³, a halogen (in oneembodiment bromine) or alkyl of from 1-4 carbons (in one embodimentmethyl), R³ can be alkyl of from 1-5 carbons, Q can be a chemical bond,at least two of L² and L³ can be connected (in one embodiment via amoiety including oxygen), and each of L¹, L⁴, and L⁵ can be H or methyl.

[0027] In another set of embodiments, the composition has a structure:

[0028] where A¹, A², A³ and A⁴ can each be independently selected fromthe group consisting of H, methyl, or a halogen, R¹, R², and R³ eachindependently comprise at least one atom, Q comprises a chemical bond oran alkyl group, and Z comprises at least one carbon atom. In oneembodiment, each of A¹, A², A³, A⁴ can be H, methyl, or a halogen, R²can be methyl or ethyl, R³ can be alkyl of from 1-8 carbons, Q can be achemical bond, and Z can be methyl or ethyl.

[0029] In another set of embodiments, the composition has a structure:

[0030] where A¹, A², A³ and A⁴ can each be independently selected fromthe group consisting of H, methyl, and a halogen, R¹, R², and R³ eachindependently comprise at least one atom, and Cy comprises anon-aromatic structure. In one embodiment, each of A¹, A², A³, A⁴ can beH, methyl, or a halogen, R² can be methyl or ethyl, R¹ can be H ormethyl, and Cy can be cyclohexyl.

[0031] In another set of embodiments, the composition has a structure:

[0032] where A¹, A², A³ and A⁴ can each be independently selected fromthe group consisting of H and a halogen, R¹, R², and R³ eachindependently comprise at least one atom, Ak comprises an alkyl group,and Cy comprises a cyclic structure. In one embodiment, each of A¹, A²,A³, A⁴ can be H, methyl, or a halogen, R² can be methyl or ethyl, R¹ canbe aromatic, R³ includes from 3-9 carbons, Cy can be an aromatic, and Akincludes from 2-4 carbons.

[0033] In another set of embodiments, the composition has a structure:

[0034] where A¹, A², A³ and A⁴ can each be independently selected fromthe group consisting of H and a halogen, R¹, R², and R³ eachindependently comprise at least one atom, and R⁴ comprises a multifusedcyclic structure. In one embodiment, each of A¹, A², A³, A⁴ can be H,methyl, or a halogen, R² can be methyl or ethyl, R¹ can be aromatic, R³can be alkyl (branched in one embodiment), R⁴ can be adamantane.

[0035] In another set of embodiments, the composition has a structure:

[0036] where A¹, A², A³ and A⁴ can each be independently selected fromthe group consisting of H and a halogen, R¹, R², and R³ eachindependently comprise at least one atom, and X comprises a halogen. Inone embodiment, each of A¹, A², A³, A⁴ can be H, methyl, or a halogen,R² can be methyl or ethyl, R¹ can be aromatic, R³ can be alkyl (branchedin one embodiment), X can be bromine or chlorine.

[0037] In another set of embodiments, the composition has a structure:

[0038] where A¹, A², A³ and A⁴ can each be independently selected fromthe group consisting of H and a halogen, R¹, R², and R³ eachindependently comprise at least one atom, and Z¹ and Z² eachindependently comprise at least one carbon atom. In one embodiment, eachof A¹, A², A³, A⁴ can be H, methyl, or a halogen, R²can be methyl orethyl, R¹ can be aromatic (optionally a dihalo aromatic), R³ includesfrom 5-7 carbons (non-branched alkyl in one embodiment), Z¹ and Z² canbe methyl or ethyl.

[0039] In another set of embodiments, the composition has a structure:

[0040] where A¹, A², A³ and A⁴ can each be independently selected fromthe group consisting of H and a halogen, R¹, R², and R³ eachindependently comprise at least one atom, and comprises at least twofused cyclic structures. In one embodiment, each of A¹, A², A³, A⁴ canbe H, methyl, or a halogen, R² can be methyl or ethyl, R¹ can bearomatic, R³ can be alkyl (branched in one embodiment), E can benaphthalenyl.

[0041] In another set of embodiments, the composition has a structure:

[0042] where A¹, A², A³ and A⁴ can each be independently selected fromthe group consisting of H and a halogen, R¹ comprises at least one atom,and R⁵ comprises a structure including a unit:

[0043] where R¹¹, R¹², R¹³, R¹⁴, R¹⁵, R¹⁶, R¹⁷, R¹⁸, R¹⁹, and R²⁰ eachindependently comprise at least one atom, J comprises a chemical bond orat least one atom, and at least one of R¹¹, R¹², R¹³, R¹⁴, R¹⁵, R¹⁶,R¹⁷, R¹⁸, R¹⁹, and R²⁰ can be substituted by J. In one embodiment, J canbe a chemical bond, each of A¹, A², A³, A⁴ can be H, methyl, or ahalogen, R¹ can be aromatic, each of R¹¹-R²⁰, other than J, can be H ormethyl or halogen (in one embodiment, each can be H). In one embodiment,J comprises at least 5 atoms.

[0044] In another set of embodiments, the composition has a structure:

[0045] where A¹, A², A³ and A⁴ can each be independently selected fromthe group consisting of H and a halogen, R¹ comprises at least one atom,and R⁵ comprises a structure including a unit:

[0046] where R¹¹, R¹², R¹³, R¹⁴, R¹⁵, R¹⁶, R¹⁷, R¹⁸, R¹⁹, R²⁰ and R²¹each independently comprise at least one atom, and J comprises achemical bond or at least one atom. In one embodiment, J can be achemical bond, each of A¹, A², A³, A⁴ can be H, methyl, or a halogen ormethyl, R¹ can be aromatic, each of R¹¹-R²¹ can be H or methyl orhalogen (in one embodiment, each can be H). In one embodiment, Jcomprises at least 5 atoms.

[0047] In another set of embodiments, the composition has a structure:

[0048] where A¹, A², A³, and A⁴ can each be independently selected fromthe group consisting of H and a halogen, G can be selected from thegroup consisting of —CH₃ and a halogen, R² and R³ each independentlycomprise at least one atom, and E comprises at least two fused cyclicstructures. In one embodiment, each of A¹, A², A³, A⁴ can be H, methyl,or a halogen, R³can be alkyl or aromatic, E includes two fused cyclicgroups (in one embodiment, one of the cyclic structures can bearomatic).

[0049] In another set of embodiments, the composition has a structure:

[0050] where A¹, A², A³, and A⁴ can each be independently selected fromthe group consisting of H and a halogen, R² and R³ each independentlycomprise at least one atom, and J comprises a chemical bond or at leastone atom. In one embodiment, each of A¹, A², A³, A⁴ can be H, methyl, ora halogen, R³ can be alkyl of from 1-7 carbons, or can be aromatic, Eincludes two fused cyclic groups (in one embodiment, one of the cyclicstructures can be aromatic). J includes from 1-8 carbons.

[0051] In another set of embodiments, the composition has a structure:

[0052] where A¹, A², A³, and A⁴ can each be independently selected fromthe group consisting of H and a halogen, X¹ and X² each independentlycomprise a halogen, Ak can be a non-heteroatom alkyl group or is free ofnon-terminal heteroatoms, and R² and R⁴ each independently comprise atleast one atom. In one embodiment, each of A¹, A², A³, A⁴ can be H,methyl, or a halogen, Ak can be an alkyl of from 5-7 carbons, R⁴ can bearomatic, X¹ and X² each can be halogens, but can be different.

[0053] In another set of embodiments, the composition has a structure:

[0054] where A¹, A², A³, and A⁴ can each be independently selected fromthe group consisting of H and a halogen, X¹ and X² each independentlycomprise a halogen, J comprises a chemical bond or at least one atom,and R², R³, R¹¹, R¹², R¹³, R¹⁴, and R¹⁵ each independently comprise atleast one atom. In one embodiment, each of A¹, A², A³, A⁴ can be H,methyl, or a halogen, R³ can be an alkyl of from 5-7 carbons, J can be achemical bond, at least three of R¹¹-R¹⁵ can be H (in one embodimenteach of R¹¹ and R¹³ can be an oxygen-containing alkyl of no more thanthan 3 carbon atoms, and in another embodiment R¹³ can be alkyl of nomore than 3 carbons and R¹¹ can be H).

[0055] In another set of embodiments, the composition has a structure:

[0056] where A¹, A², A³, and A⁴ can each be independently selected fromthe group consisting of H and a halogen, Z can be selected from thegroup consisting of H and —CH₂—CH₃, Ak can be a non-heteroatom alkylgroup or is free of non-terminal heteroatoms, and R² and R⁴ eachindependently comprise at least one atom. In one embodiment, each of A¹,A², A³, A⁴ can be H, methyl, or a halogen, R² can be methyl or ethyl, Akcan be alkyl of from 3-7 carbons (non-branched in one embodiment), R⁴can be aromatic, Z can be H or ethyl.

[0057] In another set of embodiments, the composition has a structure:

[0058] where A¹, A², A³, and A⁴ can each be independently selected fromthe group consisting of H and a halogen, X comprises a halogen, Ak canbe a non-heteroatom alkyl group or is free of non-terminal heteroatoms,and R² and R⁴ each independently comprise at least one atom. In oneembodiment, each of A¹, A², A³, A⁴ can be H, methyl, or a halogen, R²can be methyl or ethyl, Ak can be alkyl of from 3-7 carbons(non-branched in one embodiment), R⁴ can be aromatic, X can be chlorine.

[0059] In another set of embodiments, the composition has a structure:

[0060] where A¹, A², A³ and A⁴ can each be independently selected fromthe group consisting of H and a halogen, X comprises a halogen, Zcomprises an alkyl group having at least three carbon atoms, and R², R³and R⁴ each independently comprise at least one atom. In one embodiment,each of A¹, A², A³, A⁴ can be H, methyl, or a halogen, R² can be methylor ethyl, Z can be alkyl of from 3-7 carbons (non-branched in oneembodiment), R⁴ can be aromatic, X can be chlorine or bromine.

[0061] In another set of embodiments, the composition has a structure:

[0062] where A¹, A², A³, and A⁴ can each be independently selected fromthe group consisting of H and a halogen, X comprises a halogen, R³comprises a structure including at least two halogen atoms, and R² andR⁴ each independently comprise at least one atom. In one embodiment,each of A¹, A², A³, A⁴ can be H, methyl, or a halogen, R² can be methylor ethyl, R³ can be alkyl including at least 2 halogens (optinoallyaromatic including at least two halogens), R⁴ can be aromatic, X can bechlorine or bromine.

[0063] In another set of embodiments, the composition has a structure:

[0064] where A¹, A², A³, and A⁴ can each be independently selected fromthe group consisting of H and a halogen, J comprises a chemical bond orat least one atom, and R², R³, R¹¹, R¹², R¹³, R¹⁴, and R¹⁵ eachindependently comprise at least one atom. In one embodiment, each of A¹,A², A³, A⁴ can be H, methyl, or a halogen, R² can be methyl or ethyl, R³can be alkyl of from 2-7 carbons, J can be a chemical bond, R¹³ can bemethoxy, other R groups can be H, methyl, or halogen.

[0065] In another set of embodiments, the composition has a structure:

[0066] where A¹, A², A³, and A⁴ can each be independently selected fromthe group consisting of H and a halogen, Ak can be a non-heteroatomalkyl group or is free of non-terminal heteroatoms, and R² and R⁴ eachindependently comprise at least one atom. In one embodiment, each of A¹,A², A³, A⁴ can be H, methyl, or a halogen, Ak can be alkyl of from 3-5carbons, R⁴ can be aromatic. R² can be methyl or ethyl.

[0067] In another set of embodiments, the composition has a structure:

[0068] where A¹, A², A³, and A⁴ can each be independently selected fromthe group consisting of H and a halogen, J comprises a chemical bond orat least one atom, and R², R³, R¹¹, R¹², R¹³, R¹⁴, and R¹⁵ eachindependently comprise at least one atom. In one embodiment, each of A¹,A², A³, A⁴ can be H, methyl, or a halogen, R³ can be alkyl of from 3-5carbons, J can be a chemical bond, R² can be methyl or ethyl. R¹³ can bemethoxy, and other R groups can be H, halogen, or methyl.

[0069] In another set of embodiments, the composition has a structure:

[0070] where A¹, A², A³, and A⁴ can each be independently selected fromthe group consisting of H and a halogen, Ak can be a non-heteroatomalkyl group or is free of non-terminal heteroatoms, and R², R⁴, R²¹,R²², R²³, R²⁴, R²⁵, R²⁶, and R²⁷ each independently comprise at leastone atom. In one embodiment each of A¹-A⁴ and R²¹-R²⁷ can be H, methyl,or a halogen, Ak can be alkyl of from 3-5 carbons, R⁴ can be aromatic,and R² can be methyl or ethyl.

[0071] In another set of embodiments, the composition has a structure:

[0072] where A¹, A², A³, and A⁴ can each be independently selected fromthe group consisting of H and a halogen, J comprises a chemical bond orat least one atom, R², R³, R¹¹, R¹², R¹³, R¹⁴, R¹⁵, R²¹, R²², R²³, R²⁴,R²⁵, R²⁶, and R²⁷ each independently comprise at least one atom, and atleast one of R¹¹, R¹², R¹³, R¹⁴, and R¹⁵ can be substituted by T, Tcomprising at least one carbon atom. In one embodiment, J can be achemical bond, each of A¹-A⁴ and R²¹-R²⁷ can be H, methyl, or a halogen,R³ can be methyl or ethyl, J can be a chemical bond, each of R¹¹-R¹⁵that is not substituted by T can be H, methyl, or a halogen (in oneembodiment, H), and T can be methoxy, ethoxy, or isopropxy (in oneembodiment, methoxy).

[0073] In another set of embodiments, the composition has a structure:

[0074] where A¹, A², A³, and A⁴ can each be independently selected fromthe group consisting of H and a halogen, R¹ and R² each independentlycomprise at least one atom, and Ak can be a non-heteroatom alkyl groupor is free of non-terminal heteroatoms. In one embodiment, each of A¹-A⁴can be H, methyl, or a halogen, R¹ can be aromatic (in one embodiment,halogen-substituted), R² can be methyl or ethyl, Ak can be alkyl of from4-9 carbons.

[0075] In another set of embodiments, the composition has a structure:

[0076] where A¹, A², A³, and A⁴ can each be independently selected fromthe group consisting of H and a halogen, E comprises at least 2 cyclicgroups, and R² and R³ each independently comprise at least one atom.

[0077] In another set of embodiments, the composition has a structure:

[0078] where A¹, A², A³, and A⁴ can each be independently selected fromthe group consisting of H and a halogen, R¹ comprises a structureincluding at least two halogen atoms, and R² and R³ each independentlycomprise at least one atom.

[0079] In another set of embodiments, the composition has a structure:

[0080] where A¹, A², A³, A⁴, Y¹, Y², Y³, Y⁴ and Y⁵ can each beindependently selected from the group consisting of H and a halogen, andR¹ and R²each independently comprise at least one atom. In oneembodiment, each of A¹-A⁴ can be H, methyl, or a halogen, R¹ can bearomatic (in one embodiment, methoxy-substituted), R² can be methyl orethyl, Y¹-Y⁴ can each be H or methyl, with the exception that one can bea halgogen.

[0081] In another set of embodiments, the composition has a structure:

[0082] where A¹, A², A³, and A⁴ can each be independently selected fromthe group consisting of H and a halogen, J comprises a chemical bond orat least one atom, R¹, R², R³, R¹¹, R¹², R¹³, R¹⁴, R¹⁵, R¹⁶, R¹⁷, andR¹⁸ each independently comprise at least one atom, and at least one ofR¹¹, R¹², R¹³, R¹⁴, R¹⁵, R¹⁶, R¹⁷, and R¹⁸ can be interconnected with J.In one embodiment, each of A¹-A⁴ can be H, methyl, or a halogen, R¹ canbe aromatic (in one embodiment, halogen-substituted in at least onelocation), R² can be methyl or ethyl, R³ can be alkyl of from 2-5carbons, R¹¹-R¹⁸ can be H or methyl, with the exception of the one atwhich J bonds. J can be a chemical bond or N.

[0083] In another set of composition, the composition has a structureAk-Aa-Cy, where Ak can be an alkyl group, Aa comprises an amino acid,and Cy comprises a cyclic structure; in combination with apharmaceutically acceptable carrier. In one set of embodiments, Aa isselected from among glycine, isoleucine, proline, phenylalanine.

[0084] In yet another set of embodiments, the composition has astructure Cy¹-Aa-Cy², where Aa comprises an amino acid and Cy¹ and Cy²each independently comprise a cyclic structure. In one set ofembodiments, Aa is selected from among proline and phenylalanine.

[0085] In another set of embodiments, the composition has a structure:

[0086] where R¹¹, R¹², R¹³, R¹⁴, R¹⁵, R³⁰ and R³¹ each independentlycomprise at least one atom, and G¹, G², G³, G⁴, G⁵, and G⁶ eachindependently comprise at least one atom able to form at least threecovalent bonds; in combination with a pharmaceutically acceptablecarrier. In one set of embodiments, each of R¹¹, -R¹⁵ can be H, each ofR³⁰ and R³¹ includes an aromatic, G¹ can be N, and each of G²-G⁶ can beC and G⁶

[0087] In another set of embodiments, the composition has a structure:

[0088] where each of the R groups independently comprises an atom, incombination with a pharmaceutically-acceptable carrier. In one set ofembodiments, each of R⁵⁰-R⁵⁴ can be H, each of R^(40, 41, 43, 44) can beH, R⁴² can be t-butyl or ethoxy, R³⁰ can be a cyclic structure (in oneembodiment, a 7-membered ring).

[0089] In another set of embodiments, the composition has a structure:

[0090] where R¹¹, R¹², R¹³, and R⁴⁰ each independently comprise at leastone atom, G¹, G², G³, G⁴, G⁵, G⁶, G⁷, G⁸, and G⁹ each independentlycomprise at least one atom able to form at least three covalent bonds,and E comprises at least 2 cyclic groups; in combination with apharmaceutically acceptable carrier. In one set of embodiments, G⁵ andG², can be N, and all remaining G groups can be C, each of R¹¹, R¹², R¹³can be H or methyl, R⁴⁰ can be aromatic (in one embodiment a benzeme orsubstituted benzene), E comprises naphthalene.

[0091] In another set of embodiments, the composition has a structure:

[0092] where R⁶⁰, R⁶¹, R⁷⁰, R⁷¹, R⁷², R⁷³, and R⁷⁴ each independentlycomprises at least one atom, G¹, G², G³, G⁴, G⁵, G⁶, and G⁷ eachindependently comprise at least one atom able to form at least threecovalent bonds, and J comprises a chemical bond or at least one atom; incombination with a pharmaceutically acceptable carrier. In one set ofembodiments, G⁵ can be N, each of G¹-G⁶ can be C, G⁷ can be N, R⁶¹ canbe H, J comprises at least one C, each of R⁷⁰-R⁷⁴ can be H or methylexcept that R⁷² can be alkoxy. R⁶⁰ includes at least one halogen, andcan be a halogenated alkyl of no more than 3 carbons, or an aromatic (inone embodiment, including at least two fused rings).

[0093] In one aspect, the invention is defined, at least in part, by amethod. In some embodiments of the invention, the method involvestreating a human patient susceptible to or exhibiting symptoms of acancer characterized by aberrant expression of MUC1 with any of thecompositions disclosed herein. In one set of embodiments, the patient issusceptible of, but does not exhibit symptoms of, cancer characterizedby aberrant expression of MUC1. In another set of embodiments, thepatient exhibits symptoms of cancer characterized by aberrant expressionof MUC1. In some embodiments of the method, the patient is not otherwiseindicated for treatment for a cancer characterized by aberrantexpression of hedgehog.

[0094] In one set of embodiments, the method includes the step ofadministering to a patient a therapeutically effective amount of acomposition comprising a structure:

[0095] where Q comprises a chemical bond or an alkyl group, A¹, A², A³,and A⁴ can each be independently selected from the group consisting of Hand a halogen, R¹, R², R⁴, R¹¹, R¹², and R¹³ each independently compriseat least one atom. In one set of embodiments, each of A¹, A², A³, and A⁴can be H, Q can be methyl or ethyl, R¹ can be H or an aromatic group,each of R¹¹-R¹³ can be H, R² can be methyl or ethyl, R⁴ can be alkyl (inone embodiment, straight chain), an aromatic (in one embodiment,including at least two aromatic rings, optionally in branchedconfiguration).

[0096] In another set of embodiments, the method includes the step ofadministering to a patient a therapeutically effective amount of acomposition comprising a structure:

[0097] where A¹, A², A³, and A⁴ can each be independently selected fromthe group consisting of H and a halogen, J comprises a chemical bond orat least one atom, and R², R³, R¹¹, R¹², R¹³, R¹⁴, and R¹⁵ eachindependently comprise at least one atom. In one set of embodiments,each of A¹, A², A³, and A⁴ can be H, R³ can be an cyclic group or analkyl, which can be a straight chain alkyl, R² can be methyl or ethyl,each of R¹¹-R¹⁵ can be H or methyl, J comprises a chemical bond, NHCO,or CH-phenyl.

[0098] In another set of embodiments, the method includes the step ofadministering to a patient a therapeutically effective amount of acomposition comprising:

[0099] where Cy comprises a cyclic structure having at least sevenmembers, and R³⁰, R⁻, and R³² each comprise at least one atom. In oneset of embodiments, each of R³⁰ and R³¹ can be aromatic, and R³² can beH or halogen.

[0100] In another set of embodiments, the method includes the step ofadministering to a patient a therapeutically effective amount of acomposition comprising a structure:

[0101] where T comprises an alkyl group having at least two carbonatoms, A¹, A², A³, and A⁴ can each be independently selected from thegroup consisting of H and a halogen, and R¹, R², R⁴, R¹¹, R¹², R¹³, R¹⁴,and R¹⁵ each independently comprise at least one atom. In one set ofembodiments, T includes at least two carbon atoms, each of R¹¹-R¹⁵ canbe H or methyl, and R² can be methyl or ethyl, each of R¹ and R⁴ can bearomatic, which can be halogenated, R¹ can be benzene or substitutedbenzene.

[0102] In another aspect, the invention is directed to a method ofmaking any of the embodiments described herein. In yet another aspect,the invention is directed to a method of using any of the embodimentsdescribed herein.

[0103] In each aspect of the invention, whether composition, compositionincluding pharmaceutical carrier, or method of making or using acomposition, one set of embodiments includes any composition disclosedherein but specifically excluding any or all of the followingstructures, which have been demonstrated according to the screeningassay described in the Examples section, not to be effective in treatingcharacterized by aberrant expression of MUC1:

[0104] Other advantages, novel features, and objects of the inventionwill become apparent from the following detailed description ofnon-limiting embodiments of the invention when considered in conjunctionwith the accompanying drawings, which are schematic and which are notintended to be drawn to scale. In the figures, each identical or nearlyidentical component that is illustrated in various figures typically isrepresented by a single numeral. For purposes of clarity, not everycomponent is labeled in every figure, nor is every component of eachembodiment of the invention shown where illustration is not necessary toallow those of ordinary skill in the art to understand the invention. Incases where the present specification and a document incorporated byreference include conflicting disclosure, the present specificationshall control.

BRIEF DESCRIPTION OF THE DRAWINGS

[0105] Non-limiting embodiments of the present invention will bedescribed by way of example with reference to the accompanying drawingsin which:

[0106]FIG. 1 illustrates a drug screening assay of a MUC1 receptor; and

[0107]FIG. 2 is a graph illustrating effects that compositions of theinvention have on MUC1⁺ tumor cells in a cell proliferation assay.

DETAILED DESCRIPTION OF THE INVENTION

[0108] The present invention generally relates to compositions andmethods for cancer treatment and, in particular, to compositions thatare able to inhibit interactions involving the MUC1 Growth FactorReceptor or its ligands, and methods for treating patients displayingsymptoms of, or susceptible to MUC1-associated cancers. The inventionalso relates to assays or use of such compositions for the treatment ofpatients susceptible to or exhibiting symptoms characteristic of canceror tumorigenesis. Other compositions of the present invention useful forthe treatment or prevention of cancer or tumorigenesis include homologs,analogs, derivatives, enantiomers or functional equivalents. In anotheraspect, the invention relates to the discovery of a variety ofcompositions (e.g., drugs) useful for inhibition of cell proliferation,including proliferation associated with tumors such as MUC1-relatedtumors. The compositions of the present invention can be provided in akit including instructions for use of the composition for treatment ofdiseases. Assays can be performed to screen for and identify suchcompositions, and also for identifying which compositions are effectiveat various stages of the disease process.

[0109] The present invention also involves, in one aspect, methods fortreating patients susceptible to or exhibiting symptoms of a tumorigeniccondition or a condition where healthy receptor clustering has beendisrupted.

[0110] The present invention also provides for the treatment of patientsfor a condition different from cancer, including conditions that can beunrelated to cancer in some embodiments of the present invention. Thatis, if a composition of the invention is known for treatment of adifferent condition, the present invention also involves use of thatcomposition for treatment of cancer where indicated. The presentinvention also includes treatments where the dosage, delivery techniqueor vehicle, combination with other pharmaceutical compositions or lackof combination with other pharmaceutical compositions, rate ofadministration, timing of administration, or other factor differs fromthe use of the composition for treatment of the condition different fromcancer.

[0111] In another set of embodiments, the invention is particularlydirected to a patient population never before treated with drugs usefulaccording to certain methods of the invention, including patients whoare not suffering from or indicating susceptibility to abnormal cellproliferation, cancers or tumors, particularly MUC1-associated cancers.In other words, the treatment preferably is directed to patientpopulations that otherwise are free of symptoms that call for treatmentwith any of the drugs useful according to the invention.

[0112] International patent application serial number PCT/US01/12484,filed Apr. 12, 2001 by Bamdad et al, entitled “Treatment ofNeurodegenerative Disease” (International patent publication WO01/78709, published Oct. 25, 2001), International patent applicationserial number PCT/US00/01997, filed Jan. 25, 2000 by Bamdad et al.,entitled “Rapid and Sensitive Detection of Aberrant Protein Aggregationin Neurodegenerative Diseases” (International patent publication WO00/43791, published Jul. 27, 2000), and International patent applicationserial number PCT/US00/01504, filed Jan. 21, 2000 by Bamdad, et al.,entitled “Interaction of Colloid-Immobilized Species with Species onNon-Colloidal Structures” (International patent publication WO 00/34783,published Jul. 27, 2000), all are incorporated herein by reference. Alsoincorporated herein by reference are the following: International patentapplication serial no. PCT/US01/44782, filed Nov. 27, 2001, publicationWO 02/056022, pubished Jul. 18, 2002, entitled “Diagnostic TumorMarkers, Drug Screening for Tumorigenesis Inhibition, and Compositionsand Methods for Treatment of Cancer”, by Bamdad, et al., U.S. patentapplication Ser. No. 09/631,818, filed Aug. 3, 2000, entitled “Rapid andSensitive Detection of Protein Aggregation”; U.S. provisional patentapplication serial No. 60/213,763, filed Jun. 23, 2000, entitled“Detection of Binding Species with Colloidal and Non-ColloidalStructures”; U.S. provisional patent application No. 60/248,866 byBamdad, et al., filed Nov. 15, 2000, entitled “Detection of BindingSpecies with Colloidal and Non-Colloidal Structures”; U.S. provisionalpatent application No. 60/248,865 by Bamdad, et al., filed Nov. 15,2000, entitled “Endostatin-Like Angiogenesis Inhibition”; U.S.Provisional Patent Application No. 60/317,302, filed Sep. 5, 2001,entitled “Compositions and Methods of Treatment of Cancer,” by C.Bamdad, et al.; and U.S. Provisional Patent Application No. 60/376,732,filed May 1, 2002, entitled “Compositions and Methods of Treatment ofCancer,” by C. Bamdad, et al. Also incorporated by reference is anapplication filed on even date herewith, entitled “Compositions andMethods of Treatment of Cancer,” by C. Bamdad, et al.

[0113] The term “MUC1 Growth Factor Receptor” (“MGFR”) refers to theportion of the MUC1 receptor that interacts with a ligand, such as agrowth factor, to promote cell proliferation or tumorigenesis. The MGFRregion is positioned close to the cell surface and may be defined bymost or all of the Primary Sequence of the MUC1 Growth Factor Receptor(“PSMGFR”). The results of the present invention are consistent with amechanism in which the MGFR region is accessible to the ligand upon MUC1cleavage, at a site associated with tumorigenesis that causes release ofthe IBR from the cell.

[0114] The term “Interchain Binding Region” (“IBR”) refers to theportion of the MUC1 receptor that is able to bind strongly withhomologous or complementary regions of other MUC1 receptors, giving MUC1the ability to aggregate (i.e., self-aggregate) with other MUC1receptors, for example, via the IBRs of the respective receptors. Thisself-aggregation property of certain MUC1 receptors may contribute tothe clustering of some MUC1 receptors which has previously been observedin some healthy cells.

[0115] The term “cleaved IBR” refers to an IBR (or a portion thereof)that has been released, due to a cleavage event, from a MGFR molecule,leaving behind a segment that remains attached to the cell surface. Therelease of the cleaved portion of the IBR may be due to enzymaticcleavage or other cleavage events. As used herein, an IBR “at thesurface of a cell,” refers to an IBR attached to a cell surface receptoror a portion thereof that has not been shed or cleaved. The cleaved IBRof interest is a “disease-associated cleavage,” i.e., a type of cleavagethat can result in tumorigenesis or cancer.

[0116] The term “Constant Region” (“CR”) is any non-repeating sequenceof MUC1 that exists in a 1:1 ratio with the IBR and forms part of theportion of MUC that is shed upon cleavage in healthy or tumorigeniccells.

[0117] The term “repeats” is given its normal meaning in the art.

[0118] The term “Primary Sequence of the MUC1 Growth Factor Receptor”(PSMGFR) is a peptide sequence(GTINVHDVETQFNQYKTEAASPYNLTISDVSVSDVPFPFSAQSGA) that defines most or allof the MGFR.

[0119] The term “Extended Sequence of the MUC1 Growth Factor Receptor”(ESMGFR) is a peptide sequence(VQLTLAFREGTINVHDVETQFNQYKTEAASPYNLTISDVSVSDVPFPF) that defines all ofPSMGFR plus 9 amino acids of the proximal end of PSIBR.

[0120] PSIBR is a peptide sequence (GFLGLSNIKFRPGSVVVQLTLAFRE) thatdefines most or all of the IBR.

[0121] The term “separation” means physical separation from a cell,e.g., a situation in which a portion of MUC1 that was immobilized withrespect to a cell is no longer immobilized with respect to that cell.For example, in the case of cleavage of a portion of MUC1, the portionthat is cleaved is “separated” if it is free to migrate away from thecell and thereafter may be detected, for example, in a bodily fluid, orimmobilized at a location remote from the cell from which it was cleavedsuch as another cell, a lymph node, etc.

[0122] The term “aggregate” (noun) refers to a plurality of cell surfacereceptors or fragments thereof (e.g., MUC1), immobilized with respect toeach other with or without an intermediate auxiliary to the host system.This includes self-aggregation of healthy receptors at a cell surface;self-aggregation of cleaved receptors or fragments bound to each other;cleaved receptors or fragments bound to receptors or fragments attachedto a cell surface; and receptors or fragments, whether attached to acell or cleaved, immobilized with respect to each other via anintermediate auxiliary to the host. “Intermediate auxiliary to the hostsystem” includes a synthetic species such as a polymer, dendrimer, etc.,or a naturally-occurring species, which is not simply naturally presentin the host system but is added to the host system from a sourceexternal to the host system. This excludes aggregation that is theresult of an intermediate naturally present in the host system such as agrowth factor that can cause disease-associated aggregation. “Aggregate”(verb) or “aggregation” means the process of forming an aggregate(noun).

[0123] “Colloid,” as used herein, means nanoparticle, i.e. a very small,self-suspendable particles including inorganic, polymeric, and metalparticles. Typically, colloid particles are of less than 250 nm crosssection in any dimension, more typically less than 150 or 100 nm crosssection in any dimension, and preferably 10-30 nm, and can be metal (forexample, gold colloid particles), non-metal, crystalline or amorphous.As used herein this term includes the definition commonly used in thefield of biochemistry.

[0124] The term “cancer,” as used herein, may include, but is notlimited to, biliary tract cancer; bladder cancer; brain cancer includingglioblastomas and medulloblastomas; breast cancer; cervical cancer;choriocarcinoma; colon cancer; endometrial cancer; esophageal cancer;gastric cancer; hematological neoplasms including acute lymphocytic andmyelogenous leukemia; multiple myeloma; AIDS-associated leukemias andadult T-cell leukemia lymphoma; intraepithelial neoplasms includingBowen's disease and Paget's disease; liver cancer; lung cancer;lymphomas including Hodgkin's disease and lymphocytic lymphomas;neuroblastomas; oral cancer including squamous cell carcinoma; ovariancancer including those arising from epithelial cells, stromal cells,germ cells and mesenchymal cells; pancreatic cancer; prostate cancer;rectal cancer; sarcomas including leiomyosarcoma, rhabdomyosarcoma,liposarcoma, fibrosarcoma, and osteosarcoma; skin cancer includingmelanoma, Kaposi's sarcoma, basocellular cancer, and squamous cellcancer; testicular cancer including germinal tumors such as seminoma,non-seminoma (teratomas, choriocarcinomas), stromal tumors and germ celltumors; thyroid cancer including thyroid adenocarcinoma and medullarcarcinoma; and renal cancer including adenocarcinoma and Wilms' tumor.Commonly encountered cancers include breast, prostate, lung, ovarian,colorectal, and brain cancer.

[0125] The term “cancer treatment” as described herein, may include, butis not limited to, chemotherapy, radiotherapy, adjuvant therapy, or anycombination of the aforementioned methods. Aspects of treatment that mayvary include, but are not limited to dosages, timing of administrationor duration or therapy; and may or may not be combined with othertreatments, which may also vary in dosage, timing, or duration. Anothertreatment for cancer is surgery, which can be utilized either alone orin combination with any of the aforementioned treatment methods. One ofordinary skill in the medical arts may determine an appropriatetreatment for a patient.

[0126] An “agent for prevention of cancer or tumorigenesis” refers toany agent able to counteract any process associated with cancer ortumorigenesis, for example, as described herein. For example, an agentthat interacts with (e.g., binds to) MGFR is able to reduce or preventinteraction of MGFR with an agent that promotes tumorigenesis by itsinteraction with MGFR.

[0127] An “agent that reduces cleavage of a cell surface receptorinterchain binding region,” as used herein, is any composition thatprevents or reduces cleavage of the MUC1 receptor between the MGFR andthe IBR that would otherwise occur in the absence of the agent.Compositions disclosed herein may function by reducing cleavage of cellsurface receptor interchain binding regions, or may modify MGFR regions.Cleavage of the receptor between the MGFR and the IBR may be caused byactivity of one or more enzymes that are membrane-associated or soluble.Some of these enzymes are directly responsible for cleavage of thereceptor. Other enzymes can affect cleavage, for example, by modifyingMUC1 with moieties such as sugar groups or phosphates able to mask oralter a recognition epitope associated with the cleavage site. Otherenzymes may promote cleavage at a particular location, for example, bymodifying MUC1 with moieties such as sugar groups or phosphates able tocreate a recognition motif for cleavage associated with that location.One example way to select agents able to reduce cleavage of a cellsurface receptor IBR is to first identify enzymes that affect cleavagesuch as those described above, then test or screen various agents andtheir analogs for their ability to alter the activity of those enzymes.Another example way is to test agents known to affect the activity ofsimilar enzymes (e.g., from the same family or having a homologousstructure) for their ability to alter the associated site of cleavage ofMUC1, and to similarly test analogs of those agents. As another example,agents may be screened in a cell-free assay containing the enzyme andMUC1 receptors, and the rate or position of cleavage may be determinedand measured by any suitable technique, for example, by antibodyprobing, polymerase chain reaction (“PCR”) or the like. As anotherexample, without first identifying enzymes able to affect MUC1, variousagents may be screened against cells that present MUC1 for the agents'ability to alter cleavage site or the rate of cleavage of MUC1. Forexample, various agents may be screened in an assay containing wholecells that present MUC1; the aggregation potential of the cellsupernatant can then be measured as an indication of the amount of IBRremaining attached to the cleaved portion of MUC1, i.e., the degree ofcleavage between MGFR and IBR. In another example technique, variousagents may be screened in an assay containing whole cells that presentMUC1 where the cell supernatant is first removed, and the cellularresiduals tested for accessibility of the MGFR portion, e.g., by using alabeled antibody to the MGFR. Various agents suitable for use with theinvention can be chosen and identified by any suitable technique, forexample, the agents may be identified from commercially availablesources such as molecular libraries, or rationally designed based onknown agents having the same functional capacity and tested for activityusing the screening assays.

[0128] An “agent that reduces cleavage of the MUC1 receptor” is anycomposition able to prevent or reduce cleavage of the MUC1 receptor atany location. Such an agent may be used to treat a subject having canceror at risk for developing cancer, because if cleavage of the MUC1receptor is prevented, then the accessibility of the MGFR, a functionalreceptor associated with cancer, is reduced or prevented. Such agentsmay be selected by any suitable technique. For example, the agents maybe selected by exposing cells to a candidate agent and determining, inthe supernatant, the amount of cleaved MUC1 receptor present, relativeto a control.

[0129] A “subject” or a “patient,” as used herein, refers to any mammal(preferably, a human), and preferably a mammal that may be susceptibleto tumorigenesis or cancer associated with the aberrant expression ofMUC1. Examples include a human, a non-human primate, a cow, a horse, apig, a sheep, a goat, a dog, a cat or a rodent such as a mouse, a rat, ahamster, or a guinea pig. Generally, or course, the invention isdirected toward use with humans.

[0130] A “sample,” as used herein, is any cell, body tissue, or bodyfluid sample obtained from a subject. Preferred are body fluids include,for example, lymph, saliva, blood, urine, and the like. Samples oftissue and/or cells for use in the various methods described herein canbe obtained through standard methods including, but not limited to,tissue biopsy, including punch biopsy and cell scraping, needle biopsy;or collection of blood or other bodily fluids by aspiration or othersuitable methods.

[0131] As used herein, the term “hedgehog” refers to members of thehedgehog family of singling molecules that mediate certain patterningprocesses during development. For example, member of the hedgehog familycontrol left-right assymmetry, polarity in the central nervous system,organogenesis, and chondrogenesis. The hedgehog gene is involved in theregulation of neurotissues, bone and cartilage formation and repair,regulation of spermatogenesis, regulation of smooth muscle, regulationof lung, liver and other organs arising from the primitive gut,regulation of hematopoietic function, or regulation of skin and hairgrowth. The present invention is directed toward cancers arising fromaberrant expression of the MUC1, and are not directed to the inhibitionof hedgehog, for instance, by targeting the primary pathway of hedgehog.The compounds of the present invention are not currently known toinhibit hedgehog.

[0132] Any additional definitions necessary for understanding theinvention can be taken from International patent publication no. WO02/056022, referenced above.

[0133] The present invention generally involves compositions related tocancers and methods of treatment of cancers characterized by theaberrant expression of a class of cell surface receptors characterizedby interchain binding regions. One such set of cancers are those cancerscharacterized by the aberrant expression of MUC1. Much of thedescription of the invention herein involves cells that aberrantlyexpress MUC1. It is to be understood that in these instances thedescription is to be considered exemplary, and that the principles ofthe invention apply to other cell surface receptors that function by asimilar mechanism. With the disclosure herein, those of ordinary skillin the art will readily be able to identify other cell surface receptorsthat function by this or a similar mechanism, and to apply the inventionto those cancers characterized by aberrant expression of thosereceptors. The invention is based on a novel mechanism involvingaberrant expression of cell surface receptors, exemplified by MUC1,which was elucidated by the inventors.

[0134] The cell surface receptor MUC1, which is a tumor marker, isaberrantly expressed in many human cancers, including about 80% or 90%of breast tumors, and in a significant percentage of other human tumors,such as prostate, lung, ovarian, colorectal, and perhaps brain cancer.Extracellular portions of the MUC1 receptor may be cleaved or “shed” byat least one enzyme, and may be released into the bloodstream in somecases. Cleavage of the MUC1 receptor may occur at more than one site,and the site of cleavage may be associated with a propensity for cancer.On the surface of tumor cells, the pattern of expression of MUC1 may bealtered from that on healthy cells. In a healthy cell such as a cell inan epithelium, the MUC1 receptors often clustered at the apical borderof the cell. In contrast, in a tumor cell, the receptors may beexpressed or overexpressed, and distributed relatively homogeneouslyover the surface of the cell. One aspect of the present inventionfeatures the discovery that a specific region of MUC1, i.e., the IBR, isable to bind strongly to identical or homologous regions of other MUC1receptors. That is, some MUC1 receptors have the ability to aggregate(i.e., self-aggregate) with other MUC1 receptors via the IBR of therespective receptors. This self-aggregation property of certain MUC1receptors may contribute to the clustering of some MUC1 receptors whichhas previously been observed in some healthy cells. The discovery thatthe IBR portion of the MUC1 receptor self-aggregates is consistent withthe following mechanistic model for which the inventors presentsupporting evidence. In this mechanistic model, (1) receptor clusteringis associated with the healthy state, as aggregated IBR portions mayblock access of ligands such as growth factors to the extracellularportions of the MUC1 receptor acting as functional receptors; clusteringmay also block access of the intracellular regions to signaling ligands;and (2) if the MUC1 receptor is cleaved at a position that causes therelease of IBR, the critical force that keeps the receptors clusteredmay be lost and the receptors may then be free to migrate within thecell or cell membrane, or interact with modifying enzymes or secretedligands such as growth factors or other cell surface receptors; theseinteractions could involve a new multimerization state, such asdimerization, that may trigger a cell proliferation signaling cascade insome cases.

[0135] This mechanistic model suggests that in a subject with aMUC1-dependent tumor, or who is prone to developing such a tumor, theportion of the MUC1 receptor that is shed contains the IBR region of thereceptor, leaving the MGFR portion of the receptor accessible forinteractions with various ligands or growth factors. One diagnostic toolthus would consist of detecting the IBR region of the portion of theMUC1 receptor which is shed.

[0136] This model is also consistent with a mechanism whereby theportion of the MUC1 receptor that remains attached to the cell surfaceafter shedding of the IBR region, the MGFR (MUC1 Growth FactorReceptor), is able to function as a receptor for ligands that cantrigger cell proliferation. This mechanism is demonstrated herein with ashowing that (1) an interaction between a ligand and this portion of theMUC1 receptor (MGFR) triggers cell proliferation in some cases; and (2)blocking the interaction of this portion of the MUC1 receptor with aligand is able to block cell proliferation. When tumor cell lines inwhich the MUC1 receptor is homogeneously expressed across the entirecell surface are treated with an antibody raised against the MGFRportion of the MUC1 receptor, the rate of cell proliferation can begreatly enhanced. Binding of a ligand to the MGFR portion of the MUC1receptor may allow the receptor to dimerize. Thus, one effectivetherapeutic strategy may be to block the MGFR portion of the receptor,for example, with a monomeric composition, which may preventdimerization or subsequent signaling cascades. For example, a singlechain, or monovalent, antibody raised against the MGFR portion of theMUC1 receptor may be able to function as an anti-cancer therapeutic.

[0137] MUC1 comprises several regions termed herein as follows, recitedin an order starting from the region closest to the cell surface andprogressing away from the cell. In at least one U.S. provisional patentapplication (“earlier application(s)”), at least one region of MUC1 wasdefined differently. It is to be understood that the followingdefinition supercedes. Those of ordinary skill in the art willunderstand the invention in all its aspects from the description ofportions of MUC1 referred to differently in the earlier application(s)and in the current application and the relation of the earlierapplication(s) to this application. The PSMGFR was referred to in theearlier application(s) as an FLR region or peptide. The PSIBR wasreferred to in the earlier application(s) as a CM region or peptide.

[0138] One aspect of the invention is directed to a method for treatinga subject diagnosed or at risk of cancer or tumor characterized by theaberrant expression of MUC1. The treatments of the present inventioninvolve the use of compositions or “agents” as described herein. Thatis, one aspect of the invention involves a series of compositions oragents useful for treatment of cancer or tumor characterized by theaberrant expression of MUC1. These compositions may also be packaged inkits, optionally including instructions for use of the composition forthe treatment of such conditions. These and other embodiments of theinvention may also involve promotion of the treatment of cancer or tumoraccording to any of the techniques and compositions and combinations ofcompositions described herein.

[0139] One aspect of the invention provides a pharmaceutical preparationcomprising a composition comprising any of compositions shown below(numbered 1-51), optionally with a pharmaceutically active carrier:

[0140] In one embodiment, the composition comprises homologs, analogs,derivatives, enantiomers and functionally equivalent compositionsthereof of compositions 1-51. Another aspect of the present inventionprovides any of the above-mentioned compositions as being useful for thetreatment of cancer and particularly MUC1-associated cancers. In oneembodiment, particularly preferred compositions are compositions 19, 21,37, 41, 43 and 45-51.

[0141] In one aspect, the invention is defined, at least in part, bycompositions having certain structures, as further described below. Inthese structures, the term “chemical bond” refers to any type ofchemical bond, for example, a covalent bond, an ionic bond, a hydrogenbond, a van der Waals bond, a metal ligand bond, a dative bond, ahydrophobic interaction, or the like. It is to be understood that allcompositions are useful for any of the methods of treatment describedherein.

[0142] In these structures, atoms able to form at least three covalentbonds include those atoms of the carbon family (e.g., carbon, silicon,or germanium), the nitrogen family (e.g., nitrogen, phosphorus, orarsenic), or the boron family (e.g., boron, aluminum, or gallium). Insome embodiments, the atoms able to form at least three covalent bondsfound within structures of the invention are carbon, nitrogen, silicon,and phosphorus, and in certain embodiments, the atoms are carbon andnitrogen.

[0143] The term “halogen,” or equivalently, “halogen atom,” is given itsordinary meaning as used in the field of chemistry. The halogens includefluorine, chlorine, bromine, iodine, and astatine. Preferably, thehalogen atoms used in the present invention include one or more offluorine, chlorine, bromine, or iodine. In certain embodiments of theinvention, the halogen atoms found within the structure are fluorine,chlorine, and bromine; fluorine and chlorine; chlorine and bromine, or asingle type of halogen atom.

[0144] As used herein, a “saturated” bond is given its ordinary meaningas used in the field of chemistry. A saturated moiety generally does notcontain any double, triple, or higher order chemical bonds in itsstructure. The saturated moiety can contain any number or types of atoms(e.g., oxygen, carbon, nitrogen, hydrogen, or halogen atoms) in anyconfiguration, so long as the moiety contains only single bonds betweenthe atoms. For example, the saturated moiety may be an aliphaticstructure or a cyclic structure. A saturated moiety may be connected toa parent structure at one or more points. Examples of saturated moietiesinclude:

[0145] which each are connected to a parent structure at one point, or:

[0146] which is connected to a parent structure at more than one point(in this example, using ether linkages). In these structures, “Ak”refers to an alkyl group, as described below. As one example, the alkylgroup in these structures may have one, two, three, or four carbonatoms, and may be straight-chained or branched, as long as no double ortriple bonds are present. The alkyl group may also include only hydrogenatoms, or include halogen atoms as well.

[0147] Conversely, an “unsaturated” moiety is a moiety that contains atleast one higher-order chemical bond within its structure, i.e., atleast one double bond or triple bond between two atoms within itsstructure. The unsaturated moiety may contain, in some cases, more thanone double and/or triple bond within its structure, for example, as inan alkadiene or an alkenyne.

[0148] As used herein, an “alkyl” is given its ordinary meaning as usedin the field of organic chemistry. Alkyl or aliphatic groups typicallycontains any number of carbon atoms, for example, between 1 and 20carbon atoms, between 1 and 15 carbon atoms, between 1 and 10 carbonatoms, or between 1 and 5 carbon atoms. In some embodiments, the alkylgroup will contain at least 1 carbon atom, at least 2 carbon atoms, atleast 3 carbon atoms, at least 4 carbon atoms, at least 5 carbon atoms,at least 6 carbon atoms, at least 7 carbon atoms, or at least 8 carbonatoms. Typically, an alkyl group is a non-cyclic structure. In certainembodiments, the alkyl group is a methyl group or an ethyl group.

[0149] The carbon atoms may be arranged in any configuration within thealkyl moiety, for example, as a straight chain (i.e., a n-alkyl such asmethyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl,decyl, or undecyl) or a branched chain, for example, a t-butyl group, oran isoalkyl group such as isopropyl, isobutyl, ispentanyl, orisohexanyl. The alkyl moiety may contain none or any number of double ortriple bonds within its structure, for example, as in an alkene, analkyne, an alkadiene, an alkadiyne, an alkenyne, etc.

[0150] The alkyl group may contain any number of substituents. Forexample, the alkyl group may contain a halogen, an alkoxy (e.g., amethoxy, an ethoxy, a propoxy, an isopropoxy, a butoxy, a pentoxy, orthe like), an amine (e.g., a primary, secondary, or tertiary amine, forexample, an dimethylamine ethyl group), or a hydroxide as a substituent.As one example, if the alkyl group is a methyl group, then the methylgroup may be substituted to form, for instance, a halogenated methylgroup such as chloromethyl, bromomethyl, or iodomethyl. In someembodiments of the invention, more than one substituent ma y be present.For example, the alkyl group may have two or more halogen atoms (forexample, two chlorine atoms, or a chlorine and a bromine atom), ahalogen and an alkoxy group, or the like.

[0151] In some embodiments of the invention, the alkyl group may alsocontain one or more heteroatoms substituted within the alkyl group, suchas a nitrogen atom (e.g., as in an amine such as a primary, secondary,or tertiary amine) or an oxygen atom (as in an ether moiety). However,in other embodiments of the invention, the main chain of the alkyl groupis free of heteroatoms and includes carbon atoms. As used herein, theterm “heteroatoms” refers to atoms that can replace carbon atoms withinan alkyl group without affecting the connectivity of the alkyl group;these typically include oxygen and nitrogen atoms. Halogen atoms andhydrogen atoms are not considered to be heteroatoms; for example, achlorine atom can replace a hydrogen atom within an alkyl group withoutaffecting the connectivity of the alkyl group As used herein, a“non-heteroatom alkyl group” is an alkyl group which does not containany atoms at the carbon positions other than carbon. Some structures aredefined as being free of non-terminal heteroatoms. As used herein, a“non-terminal” atom is an atom within a structure that is connected toat least two different atoms having a valency greater than 1 (e.g., theatom is connected to two non-hydrogen and non-halogen atoms). Forexample, the oxygen in —CH₂—OH and the nitrogen atom in —CH₂—NH₂ are notconnected to two different atoms having a valency greater than 1, andthus are not non-terminal heteroatoms.

[0152] Similarly, a “cyclic” structure, as used herein, is given itsordinary definition in the field of organic chemistry, i.e., a structurethat contains at least one ring of atoms, and may contain more than onering of atoms. In other words, a cyclic structure has at least one chainof atoms that does not have a terminal end. The chain may have, forexample, three, four, five, six, seven, or more atoms arranged to form aring. The atoms within the chain may be carbon atoms, nitrogen atoms,oxygen atoms, silicon atoms, or any other atom that is able to bond toat least two different atoms.

[0153] In some embodiments of the invention, one or more substituentsmay be present on the cyclic structure. The substituents may be anysubstituent, as previously described in connection with alkyl moieties,for example, a halogen, an alkoxy, an amine, a hydroxide, or the like.In some embodiments, the substituents may also be alkyl groups, aspreviously described, for example, a methyl group, an ethyl group, apropyl group, and the like.

[0154] The cyclic structure may have one or more heteroatoms in someembodiments. For example, the cyclic structure may include a cyclohexaneor a cyclopentane ring having one or more heteroatoms, such as:

[0155] where the R's indicate the presence of additional atoms orsubstituents. The atoms substituted within the cyclohexane ring are ableto form at least three covalent bonds, and, if able to form fourcovalent bonds, the fourth covalent bond may be attached to any atom.

[0156] The cyclic structure may be a saturated cyclic structure (such asa cyclohexyl or a cyclopentyl structure), or an unsaturated cyclicstructure (such as a cyclohexenyl structure or an aromatic structure).Examples of aromatic structures, include, for instance, phenyl,naphthalenyl, anthacenyl, tolyl, pyridinyl, furanyl, pyrrolyl, and thelike. A “nonaromatic cyclic structure” is a structure in whicharomaticity of the cyclic structure is not present (for example, as in asaturated cyclic structure, a cycloalkenyl moiety, etc.)

[0157] In one set of embodiments, the aromatic structure includes abenzene ring. If substituents are present on the benzene ring (aspreviously discussed, for example, a halogen atom, a methyl group, amethoxy group, a trifluoromethyl group, etc.), they may be located inany position, i.e., in any ortho, meta, orpara position, relative to thepoint of attachment of the benzene ring. If more than one substituent ispresent, then the substituents may be located at any available pointwithin the benzene ring. For example, if there are two substituents,they may be located in the ortho and meta positions (i.e., in the 2,3 or2,5 positions), the ortho and para positions, in the two orthopositions, in the two meta positions, or in the meta and para positions.

[0158] In one set of embodiments, the aromatic group is a nonsubstitutedaromatic group, for example, a phenyl or a naphthalenyl group. Inanother set of embodiments, the aromatic structure is a halophenyl groupor a dihalophenyl group, for example, 3-chloro-4-flurophenyl; o-, m-, orp-chlorophenyl; 2,4-difluorophenyl; or o-, m-, or p-bromophenyl. Inanother set of embodiments, the aromatic structure is a methylphenyl ora dimethyl phenyl group, for example, o-, m-, or p-methylphenyl;2,3-dimethylphenyl; 2,4-dimethylphenyl; 2,5-dimethylphenyl. In anotherset of embodiments, the aromatic group is an alkylphenyl group, such aso-, m-, or p-methylphenyl; o-, m-, or p-ethylphenyl; 2-phenylethyl, orbenzyl. In another set of embodiments, the aromatic structure is ahalomethylphenyl group, such as 3-chloro-2-methylphenyl. In another setof embodiments, the aromatic structure is an alkoxyphenyl or adialkoxyphenyl group, for example, o-, m-, or p-isopropoxyphenyl; o-,m-, or p-methoxyphenyl; o-, m-, or p-ethoxyphenyl; or2,4-dimethoxyphenyl. In one set of embodiments, the aromatic group isfused with another ring of atoms. The second ring may be aromatic ornonaromatic. Examples include:

[0159] where the R's indicate the presence of additional atoms orsubstituents.

[0160] If the cyclic structure has more than one ring of atoms, therings may be distributed in any manner within the moiety. For example,the two rings may not share a common atom, share only one common atom(e.g., as in a spiro-structure), or share more than one atom, as in abicyclic structure or a propellane structure. If the two rings share atleast one common chemical bond between two atoms, then the rings may beconsidered to be “fused.”

[0161] One example of a fused ring system is a structure:

[0162] where a five member ring is fused to a six member ring in abicyclic arrangement, and G represents atoms each having at least threecovalent bonds, as previously discussed. In some embodiments, one orboth rings may be aromatic. As one example, a single nitrogensubstitution onto the five-member ring, when both rings are aromatic,can result in an indole moiety, for example:

[0163] Additionally, other substituents or cyclic rings may besubstituted onto the structure as well, for example, a cyclohexylmoiety.

[0164] If several rings are jointly fused to each other, then the ringsmay be considered to be “multifused.” One example of a multifusedcompound is an adamantane structure:

[0165] where the R's indicate the presence of additional atoms orsubstituents.

[0166] As used herein, when two cyclic groups are in a “branchedconfiguration,” the two cyclic groups are on different branches of acommon moiety. In other words, the two cyclic groups are not seriallyarranged relative to each other. That is, removal of either of thecyclic structures within the moiety does not automatically cause theother cyclic structure to be disconnected from the rest of the moiety.One example of this is illustrated by a diphenylmethyl moiety:

[0167] where the R's indicate the presence of additional atoms orsubstituents.

[0168] In one set of embodiments, the composition includes a substitutedurea moiety. The substituted urea moiety includes at least one cyclicstructure having at least seven members. In some cases, the cyclicstructure may be a substituted cyclic structure, for example, thestructure may include an azepane moiety or a cycloheptane structure, orthe structure may include a cycloalkone moiety, that is, an oxygen atomthat is double bonded to a member of the cyclic ring.

[0169] An “amino acid” is given its ordinary meaning as used in thefield of biochemistry. An amino acid typically has a structure:

[0170] In this structure, R may be any suitable moiety. For example, Rmay be a hydrogen atom, a methyl group, or an isopropyl group. As usedherein, the “natural amino acids” are the 20 amino acids commonly foundin nature, i.e., alanine, arginine, asparagine, aspartic acid, cysteine,glutamine, glutamic acid, glycine, histidine, isoleucine, leucine,lysine, methionine, phenylalaine, proline, serine, threonine,tryptophan, tyrosine, and valine. Similarly, an unnatural amino acid isan amino acid, where the R group does not correspond to one of thenatural amino acids.

[0171] In one embodiment, the compositions further comprise homologs,analogs, derivatives, enantiomers and functionally equivalentcompositions thereof of the compositions of the invention, for example,compositions 1-51. Such homologs, analogs, derivatives, enantiomers andfunctionally equivalent compositions thereof of the compositions may beused in any of the assays described above that are able to detect ortreat cancer, particularly MUC1-associated cancers. “Functionallyequivalent” generally refers to a composition capable of treatment ofpatients having MUC1-associated cancer, or of patients susceptible toMUC1-associated cancers. It will be understood that the skilled artisanwill be able to manipulate the conditions in a manner to prepare suchhomologs, analogs, derivatives, enantiomers and functionally equivalentcompositions.

[0172] Homologs, analogs, derivatives, enantiomers and functionallyequivalent compositions which are about as effective or more effectivethan the parent compound are also intended for use in the method of theinvention. Such compositions may also be screened by the assaysdescribed herein for increased potency and specificity towards thecancer characterized by aberrant expression of MUC1, preferably withlimited side effects. Synthesis of such compositions may be accomplishedthrough typical chemical modification methods such as those routinelypracticed in the art.

[0173] Another aspect of the present invention involves a methodcomprising providing any of the compositions of the present invention,and performing a combinatorial synthesis on the composition, preferablyto obtain homologs, analogs, derivatives, enantiomers and functionallyequivalent compositions thereof of the composition. An assay may beperformed with the homolog, analog, derivative, enantiomer orfunctionally equivalent composition to determine its effectiveness ininhibiting cancer characterized by aberrant expression of MUC1. Thecombinatorial synthesis can involve subjecting a plurality of thecompositions described herein to combinatorial synthesis.

[0174] Another aspect provides a method of administering any compositionof the present invention to a subject. When administered, thecompositions of the invention are applied in pharmaceutically acceptableamounts and as pharmaceutically acceptable compositions. Suchpreparations may routinely contain salts, buffering agents,preservatives, compatible carriers or other therapeutic ingredients.Examples of well-known carriers include glass, polystyrene,polypropylene, polyethylene, dextran, nylon, amylase, natural andmodified cellulose, polyacrylamide, agarose and magnetite. The nature ofthe carrier can be either soluble or insoluble. Those skilled in the artwill know of other suitable carriers, or will be able to ascertain such,using only routine experimentation.

[0175] In some cases, the present invention includes the step ofbringing a composition of the invention into association or contact witha suitable carrier, which may constitute one or more accessoryingredients. The final compositions may be prepared by any suitabletechnique, for example, by uniformly and intimately bringing thecomposition into association with a liquid carrier, a finely dividedsolid carrier or both, optionally with one or more formulationingredients such as buffers, emulsifiers, diluents, excipients, dryingagents, antioxidants, preservatives, binding agents, chelating agents,or stabilizers and then, if necessary, shaping the product.

[0176] In some embodiments, the compositions of the present inventionmay be present as a pharmaceutically acceptable salt. The term“pharmaceutically acceptable salts” includes salts of the composition,prepared, for example, with acids or bases, depending on the particularsubstituents found within the composition and the treatment modalitydesired. Pharmaceutically acceptable salts can be prepared as alkalinemetal salts, such as lithium, sodium, or potassium salts; or as alkalineearth salts, such as beryllium, magnesium or calcium salts. Examples ofsuitable bases that may be used to form salts include ammonium, ormineral bases such as sodium hydroxide, lithium hydroxide, potassiumhydroxide, calcium hydroxide, magnesium hydroxide, and the like.Examples of suitable acids that may be used to form salts includeinorganic or mineral acids such as hydrochloric, hydrobromic,hydroiodic, hydrofluoric, nitric, carbonic, monohydrogencarbonic,phosphoric, monohydrogenphosphoric, dihydrogenphosphoric, sulfuric,monohydrogensulfuric, phosphorous acids and the like. Other suitableacids include organic acids, for example, acetic, propionic, isobutyric,maleic, malonic, benzoic, succinic, suberic, fumaric, mandelic,phthalic, benzenesulfonic, p-tolylsulfonic, citric, tartaric,methanesulfonic, glucuronic, galactunoric, salicylic, formic,naphthalene-2-sulfonic, and the like. Still other suitable acids includeamino acids such as arginate, aspartate, glutamate, and the like.

[0177] In general, pharmaceutically acceptable carriers for arewell-known to those of ordinary skill in the art. As used herein, a“pharmaceutically acceptable carrier” refers to a non-toxic materialthat does not significantly interfere with the effectiveness of thebiological activity of the active ingredient or ingredients.Pharmaceutically acceptable carriers include, for example, diluents,emulsifiers, fillers, salts, buffers, excipients, drying agents,antioxidants, preservatives, binding agents, bulking agents, chelatingagents, stabilizers, solubilizers, and other materials well-known in theart. Examples of suitable formulation ingredients include diluents suchas calcium carbonate, sodium carbonate, lactose, kaolin, calciumphosphate, or sodium phosphate; granulating and disintegrating agentssuch as corn starch or algenic acid; binding agents such as starch,gelatin or acacia; lubricating agents such as magnesium stearate,stearic acid, or talc; time-delay materials such as glycerolmonostearate or glycerol distearate; suspending agents such as sodiumcarboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose,sodiumalginate, polyvinylpyrrolideone; dispersing or wetting agents suchas lecithin or other naturally-occurring phosphatides; or thickeningagents such as cetyl alcohol or beeswax. The compositions of theinvention may be formulated into preparations in solid, semi-solid,liquid or gaseous forms such as tablets, capsules, elixrs, powders,granules, ointments, solutions, depositories, inhalants or injectables.The compositions of the present invention may be delivered by anysuitable delivery method, for example, oral, parenteral or surgicaladministration. The invention also embraces locally administering thecompositions of the invention, for example, as implants

[0178] Preparations include sterile aqueous or nonaqueous solutions,suspensions and emulsions. Examples of nonaqueous solvents are propyleneglycol, polyethylene glycol, vegetable oil such as olive oil, aninjectable organic esters such as ethyloliate. Aqueous carriers includewater, alcoholic/aqueous solutions, emulsions or suspensions, includingsaline and buffered media. Parenteral vehicles include sodium chloridesolution, Ringer's dextrose, dextrose and sodium chloride, lactatedRinger's or fixed oils. Intravenous vehicles include fluid and nutrientreplenishers, electrolyte replenishers, (such as those based on Ringer'sdextrose), and the like. Preservatives and other additives may also bepresent such as, for example, antimicrobials, antioxidants, chelatingagents and inert gases and the like. Those of skill in the art canreadily determine the various parameters for preparing thesepharmaceutical compositions without resort to undue experimentation.

[0179] The compositions of the invention may be administered singly orin combination with other compositions of the invention or othercompositions. For example, in one embodiment, compositions of theinvention are administered in combination with agents that block cellsurface receptors, such as the alpha-V-beta-3 cell surface receptor.

[0180] According to the methods of the invention, the compositions ofthe invention can be administered by injection by gradual infusion overtime or by any other medically acceptable mode. Any medically acceptablemethod may be used to administer the composition to the patient. Theparticular mode selected will depend of course, upon factors such as theparticular drug selected, the severity of the state of the subject beingtreated, or the dosage required for therapeutic efficacy. The methods ofthis invention, generally speaking, may be practiced using any mode ofadministration that is medically acceptable, meaning any mode thatproduces effective levels of the active composition without causingclinically unacceptable adverse effects.

[0181] The administration may be localized (i.e., to a particularregion, physiological system, tissue, organ, or cell type) or systemic,depending on the condition to be treated. For example, the compositionmay be administered through parental injection, implantation, orally,vaginally, rectally, buccally, pulmonary, topically, nasally,transdermally, surgical administration, or any other method ofadministration where access to the target by the composition isachieved. Examples of parental modalities that can be used with theinvention include intravenous, intradermal, subcutaneous, intracavity,intramuscular, intraperitoneal, epidural, or intrathecal. Examples ofimplantation modalities include any implantable or injectable drugdelivery system. Oral administration may be preferred for sometreatments because of the convenience to the patient as well as thedosing schedule. Compositions suitable for oral administration may bepresented as discrete units such as capsules, pills, cachettes, tables,or lozenges, each containing a predetermined amount of the activecompound. Other oral compositions include suspensions in aqueous ornon-aqueous liquids such as a syrup, an elixir, or an emulsion.

[0182] The compositions of the present invention may be given indosages, generally, at the maximum amount while avoiding or minimizingany potentially detrimental side effects. The compositions can beadministered in effective amounts, alone or in a cocktail with othercompounds, for example, other compounds that can be used to treatcancer. An effective amount is generally an amount sufficient to inhibitMUC1-associated cancer within the subject.

[0183] One of skill in the art can determine what an effective amount ofthe composition is by screening the ability of the composition using anyof the assays described herein. The effective amounts will depend, ofcourse, on factors such as the severity of the condition being treated;individual patient parameters including age, physical condition, sizeand weight; concurrent treatments; the frequency of treatment; or themode of administration. These factors are well known to those ofordinary skill in the art and can be addressed with no more than routineexperimentation. It is generally preferred that a maximum dose be used,that is, the highest safe dose according to sound medical judgment.

[0184] Dosages may be estimated based on the results of experimentalmodels, optionally in combination with the results of assays of thepresent invention. Generally, daily oral prophylactic doses of activecompounds will be from about 0.01 mg/kg per day to 2000 mg/kg per day.Oral doses in the range of 10 to 500 mg/kg, in one or severaladministrations per day, may yield suitable results. In the event thatthe response of a particular subject is insufficient at such doses, evenhigher doses (or effective higher doses by a different, more localizeddelivery route) may be employed to the extent that patient tolerancepermits. Multiple doses per day are also contemplated in some cases toachieve appropriate systemic levels of the composition.

[0185] In administering the compositions of the invention to subjects,dosing amounts, dosing schedules, routes of administration and the likemay be selected so as to affect other known activities of thesecompositions. For example, amounts, dosing schedules and routes ofadministration may be selected as described herein, wherebytherapeutically effective levels for the inhibition or treatment ofMUC1-associated cancers are provided, yet therapeutically effectivelevels for alternative treatments are not provided.

[0186] Other delivery systems suitable for use with the presentinvention include time-release, delayed release, sustained release, orcontrolled release delivery systems. Such systems may avoid repeatedadministrations of the active compounds of the invention in many cases,increasing convenience to the subject and the physician. Many types ofrelease delivery systems are available and known to those of ordinaryskill in the art. They include, for example, polymer based systems suchas polylactic and/or polyglycolic acid, polyanhydrides, andpolycaprolactone; nonpolymer systems that are lipid-based includingsterols such as cholesterol, cholesterol esters, and fatty acids orneutral fats such as mono-, di- and triglycerides; hydrogel releasesystems; silastic systems; peptide based systems; wax coatings;compressed tablets using conventional binders and excipients; orpartially fused implants. Specific examples include, but are not limitedto, erosional systems in which the composition is contained in a formwithin a matrix, or diffusional systems in which an active componentcontrols the release rate. The formulation may be as, for example,microspheres, hydrogels, polymeric reservoirs, cholesterol matrices, orpolymeric systems. In some embodiments, the system may allow sustainedor controlled release of the active compound to occur, for example,through control of the diffusion or erosion/degradation rate of theformulation. In addition, a pump-based hardware delivery system may beused in some embodiment of the invention.

[0187] Use of a long-term release implant may be particularly suitablein some cases. “Long-term release,” as used herein, means that theimplant is constructed and arranged to deliver therapeutic levels of thecomposition for at least 30 or 45 days, and preferably at least 60 or 90days, or even longer in some cases. Long-term release implants are wellknown to those of ordinary skill in the art, and include some of therelease systems described above.

[0188] The present invention also provides any of the above-mentionedcompositions useful for treatment of cancer characterized by aberrantexpression of MUC packaged in kits, optionally including instructionsfor use of the composition for the treatment of cancer. That is, the kitcan include a description of use of the composition for participation inany biological or chemical mechanism disclosed herein associated withcancer or tumor. The kits can further include a description of activityof cancer characterized by aberrant expression of MUC1 in treating thepathology, as opposed to the symptoms of the cancer. That is, the kitcan include a description of use of the compositions as discussedherein. The kit also can include instructions for use of a combinationof two or more compositions of the invention. Instructions also may beprovided for administering the drug by any suitable technique, such asorally, intravenously, directly into the cerebrospinal fluid via aspinal drip, pump or implantable delivery device, or via another knownroute of drug delivery. The invention also involves promotion of thetreatment of cancer characterized by aberrant expression of MUC1according to any of the techniques and compositions and compositioncombinations described herein.

[0189] The compositions of the invention, in some embodiments, may bepromoted for treatment of abnormal cell proliferation, cancers, ortumors, particularly MUC1-associated cancers or includes instructionsfor treatment of accompany cell proliferation, cancers, or tumors,particularly MUC1-associated cancers as mentioned above. In anotheraspect, the invention provides a method involving promoting theprevention or treatment of cancer via administration of any one of thecompositions of the present invention, and homologs, analogs,derivatives, enantiomers and functionally equivalent compositionsthereof in which the composition is able to treat MUC1-associatedcancers. As used herein, “promoted” includes all methods of doingbusiness including methods of education, hospital and other clinicalinstruction, pharmaceutical industry activity including pharmaceuticalsales, and any advertising or other promotional activity includingwritten, oral and electronic communication of any form, associated withcompositions of the invention in connection with treatment of cellproliferation, cancers or tumors. “Instructions” can define a componentof promotion, and typically involve written instructions on orassociated with packaging of compositions of the invention. Instructionsalso can include any oral or electronic instructions provided in anymanner. The “kit” typically defines a package including any one or acombination of the compositions of the invention and the instructions,or homologs, analogs, derivatives, enantiomers and functionallyequivalent compositions thereof, but can also include the composition ofthe invention and instructions of any form that are provided inconnection with the composition in a manner such that a clinicalprofessional will clearly recognize that the instructions are to beassociated with the specific composition.

[0190] The kits described herein may also contain one or morecontainers, which can contain compounds such as the species, signalingentities, biomolecules and/or particles as described. The kits also maycontain instructions for mixing, diluting, and/or administrating thecompounds. The kits also can include other containers with one or moresolvents, surfactants, preservative and/or diluents (e.g., normal saline(0.9% NaCl), or 5% dextrose) as well as containers for mixing, dilutingor administering the components to the sample or to the patient in needof such treatment.

[0191] The compositions of the kit may be provided as any suitable form,for example, as liquid solutions or as dried powders. When thecomposition provided is a dry powder, the powder may be reconstituted bythe addition of a suitable solvent, which may also be provided. Inembodiments where liquid forms of the composition are sued, the liquidform may be concentrated or ready to use. The solvent will depend on thecompound and the mode of use or administration. Suitable solvents fordrug compositions are well known and are available in the literature.The solvent will depend on the compound and the mode of use oradministration.

[0192] The kit, in one set of embodiments, may comprise a carrier meansbeing compartmentalized to receive in close confinement one or morecontainer means such as vials, tubes, and the like, each of thecontainer means comprising one of the separate elements to be used inthe method. For example, one of the container means may comprise apositive control in the assay. Additionally, the kit may includecontainers for other components, for example, buffers useful in theassay.

[0193] The function and advantage of these and other embodiments of thepresent invention will be more fully understood from the examples below.The following examples are intended to illustrate the benefits of thepresent invention, but do not exemplify the full scope of the invention.

EXAMPLE 1

[0194] This example illustrates high-throughput drug screen thatidentifies compounds able to inhibit interactions involving the MUC1receptor and/or its ligands. A lysate is prepared from MUC1⁺ breasttumor cells. In the drug screening assay, described below, this lysateprovides ligands and/or co-receptors that interact with the MGFR portionof the MUC1 receptor. FIG. 1 is an illustration of the drug screeningassay.

[0195] A cell pellet from a cell culture flask approximately 75%confluent with T47D cells (ATCC # HTB-133—a MUC⁺ breast tumor cell line)is prepared for each experiment. The cell pellet is optionally frozen at−20° C. before use. The cells are pelleted at 4° C. in a centrifuge, andthe supernatant is removed with disturbing the cells.

[0196] The cell pellet is then washed in phosphate-buffered saline andresuspended in additional cold saline. The number of cells is determinedand the volume is adjusted such that the cell pellet containsapproximately 1 million cells.

[0197] The cells are resuspended into 2 mL of saline, then sonicated for30 second to lyse the cells. The lysate is then separated and pelletedin a centrifuge. The supernatant, containing soluble proteins of thecell lysate, is then removed and stored.

[0198] Colloids, which will present the MGFR portion of the MUC1receptor, are prepared as follows. 6 mL of Auro dye Forte gold colloidsare derivatized such that the colloids bear self-assembled monolayers(SAMs) that present approximately 3% NTA-Ni²⁺, using methods describedin International patent application serial number PCT/US00/01997, filedJan. 25, 2000, byBamdad et al., entitled “Rapid and Sensitive Detectionof Aberrant Protein Aggregation in Neurodegenerative Diseases”(International patent publication WO 00/43791, published Jul. 27, 2000),and International patent application serial number PCT/US00/01504, filedOct. 21, 2000 by Bamdad, et al., “Interaction of Colloid-ImmobilizedSpecies with Species on Non-Colloidal Structures” (International patentpublication WO 00/34783, published Jul. 27, 2000).

[0199] The colloids are separated into 24 aliquots, each containing 200microliters. To 23 of the aliquots, 20 microliters of histidine taggedprimary sequence (PS)MGFR peptide(GTINVHDVETQFNQYKTEAASPYNLTISDVSVSDVPFPFSAQSGAHHHHHH) at 100 micromolarconcentration, are added, and the aliquots incubated at room temperaturefor about 10 min. To the remaining aliquot, 20 microliters of a negativecontrol peptide, histidine-tagged GRGDS peptide(HHHHHHSSSSGSSSSGSSSSGGRGDSGRGDS) solution at 100 micromolarconcentration are added.

[0200] The colloids are centrifuged for approximately 15 minutes. Thesupernatant is then removed and the colloid pellet is resuspended in 100microliters of phosphate buffer.

[0201] The drug screen is performed as follows. Into each sample well,65 microliters of lysate and 5 microliters of drug are added. About 30microliters of histidine-tagged PSMGFR-presenting colloids are thenadded to the well. Observations of the well are recorded using a digitalcamera. The plate is observed for a period of about 1 hour, and colordifferences are noted.

[0202] The positive controls turn purple or blue, while the negativecontrols remain pink. If the drug does not bind to PSMGFR or MGFR or theligand to MGFR, the well will turn purple/blue. Conversely, if the druginhibits the interaction between MGFR and its ligand(s), the well willremain pink. Thus, this example illustrates one way to perform a MUC1drug screening assay.

EXAMPLE 2

[0203] In this example, cells are counted in a cell proliferation assayin an embodiment of the invention.

[0204] Cells (e.g., T47D or K293) are plated in 96 well plates in 100 μLof the appropriate media to about 25% confuency. After allowing thecells to be in culture overnight, the cells are counted (in triplicate)to determine the 0 hour cell count. For this purpose, the media isremoved and the cells detached with trypsin in a defined volume.

[0205] The cells are then counted using a counting chamber (e.g., ahemocytometer). To the remaining wells, 5 microliters of the specificcompounds (or a control, such as dimethyl sulfoxide) are added intriplicate. After 48 hours of culture, the media is removed, then thecells detached with trypsin and counted again using a counting chamberto obtain the 48 hour cell count.

[0206]FIG. 2 is a graph showing the inhibitory effect of certaincompositions of the invention on the proliferation of MUC1⁺ cells. TheMUC1⁺ cells used in this experiment were T47D cells (a breast tumor cellline) and the control cells were K293 cells from an embryonic kidneycell line.

[0207] While several embodiments of the invention have been describedand illustrated herein, those of ordinary skill in the art will readilyenvision a variety of other means and structures for performing thefunctions and/or obtaining the results or advantages described herein,and each of such variations or modifications is deemed to be within thescope of the present invention. More generally, those skilled in the artwould readily appreciate that all parameters, dimensions, materials, andconfigurations described herein are meant to be exemplary and thatactual parameters, dimensions, materials, and configurations will dependupon specific applications for which the teachings of the presentinvention are used. Those skilled in the art will recognize, or be ableto ascertain using no more than routine experimentation, manyequivalents to the specific embodiments of the invention describedherein. It is, therefore, to be understood that the foregoingembodiments are presented by way of example only and that, within thescope of the appended claims and equivalents thereto, the invention maybe practiced otherwise than as specifically described. The presentinvention is directed to each individual feature, system, materialand/or method described herein. In addition, any combination of two ormore such features, systems, materials and/or methods, if such features,systems, materials and/or methods are not mutually inconsistent, isincluded within the scope of the present invention.

[0208] In the claims (as well as in the specification above), alltransitional phrases such as “comprising,” “including,” “carrying,”“having,” “containing,” “involving,” and the like are to be understoodto be open-ended, i.e. to mean including but not limited to. Only thetransitional phrases “consisting of” and “consisting essentially of”shall be closed or semi-closed transitional phrases, respectively, asset forth in the United States Patent Office Manual of Patent ExaminingProcedures, section 2111.03.

What is claimed is:
 1. A composition, comprising a structure:

wherein A¹, A², A³, A⁴, Y¹, Y², and Y³ are each independently selectedfrom the group consisting of h and a halogen, G consists of one carbonatom, and R², R³ and R⁴ each independently comprise at least one atom.2. A composition, comprising a structure:

wherein A¹, A², A³ and A⁴ are each independently selected from the groupconsisting of H and a halogen, Z comprises at least three carbon atoms,and R², R³ and R⁴ each independently comprise at least one atom.
 3. Acomposition, comprising a structure:

wherein A¹, A², A³ and A⁴ are each independently selected from the groupconsisting of H and a halogen, R¹, R², and R⁴ each independentlycomprise at least one atom, and R³ comprises an branched alkyl group orat least 6 carbon atoms.
 4. A composition, comprising a structure:

wherein A¹, A², A³, A⁴, Y¹, and Y² are each independently selected fromthe group consisting of H and a halogen, R¹, R², and R³ eachindependently comprise at least one atom, Q comprises a chemical bond oran alkyl group, and X comprises a halogen.
 5. A composition, comprisinga structure:

wherein A¹, A², A³ and A⁴ are each independently selected from the groupconsisting of H and a halogen, R¹, R², and R³ each independentlycomprise at least one atom, Q comprises a chemical bond or an alkylgroup, and E comprises at least 2 cyclic groups in a branchedconfiguration.
 6. A composition, comprising a structure:

wherein A¹, A², A³ and A⁴ are each independently selected from the groupconsisting of H and a halogen, R², R³, R¹¹, R¹², R¹³, R¹⁴, and R¹⁵ eachindependently comprise at least one atom, Q comprises a chemical bond oran alkyl group, and at least two of L¹, L², L³, L⁴, and L⁵ areinterconnected via a saturated moiety.
 7. A composition, comprising astructure:

wherein A¹, A², A³ and A⁴ are each independently selected from the groupconsisting of H and a halogen, R¹, R², and R³ each independentlycomprise at least one atom, Q comprises a chemical bond or an alkylgroup, and Z comprises at least one carbon atom.
 8. A composition,comprising a structure:

wherein A¹, A², A³ and A⁴ are each independently selected from the groupconsisting of H and a halogen, R¹, R², and R³ each independentlycomprise at least one atom, and Cy comprises a nonaromatic cyclicstructure.
 9. A composition, comprising a structure:

wherein A¹, A², A³ and A⁴ are each independently selected from the groupconsisting of H and a halogen, R¹, R², and R³ each independentlycomprise at least one atom, Ak comprises an alkyl group, and Cycomprises a cyclic structure.
 10. A composition, comprising a structure:

wherein A¹, A², A³ and A⁴ are each independently selected from the groupconsisting of H and a halogen, R¹, R², and R³ each independentlycomprise at least one atom, and R⁴ comprises a multifused cyclicstructure.
 11. A composition, comprising a structure:

wherein A¹, A², A³ and A⁴ are each independently selected from the groupconsisting of H and a halogen, R¹, R², and R³ each independentlycomprise at least one atom, and X comprises a halogen.
 12. Acomposition, comprising a structure:

wherein A¹, A², A³ and A⁴ are each independently selected from the groupconsisting of H and a halogen, R¹, R², and R³ each independentlycomprise at least one atom, and Z¹ and Z² each independently comprise atleast one carbon atom.
 13. A composition, comprising a structure:

wherein A¹, A², A³ and A⁴ are each independently selected from the groupconsisting of H and a halogen, R¹, R², and R³ each independentlycomprise at least one atom, and E comprises at least two fused cyclicstructures.
 14. A composition, comprising a structure:

wherein A¹, A², A³ and A⁴ are each independently selected from the groupconsisting of H and a halogen, R¹ comprises at least one atom, and R⁵comprises a structure including a unit.

wherein R¹¹, R¹², R¹³, R¹⁴, R¹⁵, R¹⁶, R¹⁷, R¹⁸, R¹⁹, and R²⁰ eachindependently comprise at least one atom, J comprises a chemical bond orat least one atom, and at least one of R¹¹, R¹², R¹³, R¹⁴, R¹⁵, R¹⁶,R¹⁷, R¹⁸, R¹⁹, and R²⁰ is substituted by J.
 15. A composition,comprising a structure:

wherein A¹, A², A³ and A⁴ are each independently selected from the groupconsisting of H and a halogen, R¹ comprises at least one atom, and R⁵comprises a structure including a unit.

wherein R¹¹, R¹², R¹³, R¹⁴, R¹⁵, R¹⁶, R¹⁷, R¹⁹, R²⁰ and R²¹ eachindependently comprise at least one atom, and J comprises a chemicalbond or at least one atom.
 16. A method, comprising: treating a humanpatient susceptible to or exhibiting symptoms of a cancer characterizedby aberrant expression of MUC1, by administering to the patient atherapeutically effective amount of a composition comprising astructure:

wherein T comprises an alkyl group having at least two carbon atoms, A¹,A², A³, and A⁴ are each independently selected from the group consistingof H and a halogen, R¹, R², R⁴, R¹¹, R¹², R¹³, R¹⁴, and R¹⁵ eachindependently comprise at least one atom, and the patient is nototherwise indicated for treatment for a cancer characterized by aberrantexpression of hedgehog.
 17. A method, comprising: treating a humanpatient susceptible to or exhibiting symptoms of a cancer characterizedby aberrant expression of MUC1, by administering to the patient atherapeutically effective amount of a composition comprising astructure:

wherein Q comprises a chemical bond or an alkyl group, A¹, A², A³, andA⁴ are each independently selected from the group consisting of H and ahalogen, R¹, R², R⁴, R¹¹, R¹², and R¹³ each independently comprise atleast one atom, and the patient is not otherwise indicated for treatmentfor a cancer characterized by aberrant expression of hedgehog.
 18. Acomposition, comprising a structure:

wherein A¹, A², A³, and A⁴ are each independently selected from thegroup consisting of H and a halogen, G is selected from the groupconsisting of CH₃ and a halogen, R² and R³ each independently compriseat least one atom, and E comprises at least two fused cyclic structures.19. A composition, comprising a structure:

wherein A¹, A², A³, and A⁴ are each independently selected from thegroup consisting of H and a halogen, R² and R³ each independentlycomprise at least one atom, and J comprises a chemical bond or at leastone atom.
 20. A method, comprising: treating a human patient susceptibleto or exhibiting symptoms of a cancer characterized by aberrantexpression of MUC1, by administering to the patient a therapeuticallyeffective amount of a composition comprising a structure:

wherein A¹, A², A³, and A⁴ are each independently selected from thegroup consisting of H and a halogen, J comprises a chemical bond or atleast one atom, R², R³, R¹¹, R¹², R¹³, R¹⁴, and R¹⁵ each independentlycomprise at least one atom, and the patient is not otherwise indicatedfor treatment for a cancer characterized by aberrant expression ofhedgehog.
 21. A composition, comprising a structure:

wherein A¹, A², A³, and A⁴ are each independently selected from thegroup consisting of H and a halogen, X¹ and X² each independentlycomprise a halogen, Ak is a non-heteroatom alkyl group, and R² and R⁴each independently comprise at least one atom.
 22. A composition,comprising a structure:

wherein A¹, A², A³, and A⁴ are each independently selected from thegroup consisting of H and a halogen, X¹ and X² each independentlycomprise a halogen, J comprises a chemical bond or at least one atom,and R², R³, R¹¹, R¹², R¹³, R¹⁴, and R¹⁵ each independently comprise atleast one atom.
 23. A composition, comprising a structure:

wherein A¹, A², A³, and A⁴ are each independently selected from thegroup consisting of H and a halogen, Z is selected from the groupconsisting of H and —CH₂—CH₃, Ak is a non-heteroatom alkyl group, and R²and R⁴ each independently comprise at least one atom.
 24. A composition,comprising a structure:

wherein A¹, A², A³, and A⁴ are each independently selected from thegroup consisting of H and a halogen, X comprises a halogen, Ak is anon-heteroatom alkyl group, and R² and R⁴ each independently comprise atleast one atom.
 25. A composition, comprising a structure:

wherein A¹, A², A³ and A⁴ are each independently selected from the groupconsisting of H and a halogen, X comprises a halogen, Z comprises analkyl group having at least three carbon atoms, and R², R³ and R⁴ eachindependently comprise at least one atom.
 26. A composition, comprisinga structure:

wherein A¹, A², A³, and A⁴ are each independently selected from thegroup consisting of H and a halogen, X comprises a halogen, R³ comprisesa structure including at least two halogen atoms, and R² and R⁴ eachindependently comprise at least one atom.
 27. A composition, comprisinga structure:

wherein A¹, A², A³, and A⁴ are each independently selected from thegroup consisting of H and a halogen, J comprises a chemical bond or atleast one atom, and R², R³, R¹¹, R¹², R¹³, R¹⁴, and R¹⁵ eachindependently comprise at least one atom.
 28. A composition, comprisinga structure:

wherein A¹, A², A³, and A⁴ are each independently selected from thegroup consisting of H and a halogen, Ak is a non-heteroatom alkyl group,and R² and R⁴ each independently comprise at least one atom.
 29. Acomposition, comprising a structure:

wherein A¹, A², A³, and A⁴ are each independently selected from thegroup consisting of H and a halogen, J comprises a chemical bond or atleast one atom, and R², R³, R¹¹, R¹², R¹³, R¹⁴, and R¹⁵ eachindependently comprise at least one atom.
 30. A composition, comprisinga structure:

wherein A¹, A², A³, and A⁴ are each independently selected from thegroup consisting of H and a halogen, Ak is a non-heteroatom alkyl group,and R², R⁴, R²¹, R²², R²³, R²⁴, R²⁵, R²⁶, and R²⁷ each independentlycomprise at least one atom.
 31. A composition, comprising a structure:

wherein A¹, A², A³, and A⁴ are each independently selected from thegroup consisting of H and a halogen, J comprises a chemical bond or atleast one atom, R², R³, R¹¹, R¹², R¹³, R¹⁴, R¹⁵, R²¹, R²², R²³, R²⁴,R²⁵, R²⁶, and R²⁷ each independently comprise at least one atom, and atleast one of R¹¹, R¹², R¹³, R¹⁴, and R¹⁵ is substituted by T, Tcomprising at least one carbon atom.
 32. A composition, comprising astructure:

wherein A¹, A², A³, and A⁴ are each independently selected from thegroup consisting of H and a halogen, R¹ and R² each independentlycomprise at least one atom, and Ak is a non-heteroatom alkyl group. 33.A composition, comprising a structure:

wherein A¹, A², A³, and A⁴ are each independently selected from thegroup consisting of H and a halogen, E comprises at least 2 cyclicgroups, and R² and R³ each independently comprise at least one atom. 34.A composition, comprising a structure:

wherein A¹, A², A³, and A⁴ are each independently selected from thegroup consisting of H and a halogen, R¹ comprises a structure includingat least two halogen atoms, and R² and R³ each independently comprise atleast one atom.
 35. A composition, comprising a structure:

wherein A¹, A², A³, A⁴, Y¹, Y², Y³, Y⁴ and Y⁵ are each independentlyselected from the group consisting of H and a halogen, and R¹ and R²each independently comprise at least one atom.
 36. A composition,comprising a structure:

wherein A¹, A², A³, and A⁴are each independently selected from the groupconsisting of H and a halogen, J comprises a chemical bond or at leastone atom, R¹, R², R³, R¹¹, R¹², R¹³, R¹⁴, R¹⁵, R¹⁶, R¹⁷, and R¹⁸eachindependently comprise at least one atom, and at least one of R¹¹, R¹³,R¹⁴, R¹⁵, R¹⁶, R¹⁷, and R¹⁸ is interconnected with J.
 37. A method,comprising: treating a human patient susceptible to or exhibitingsymptoms of a cancer characterized by aberrant expression of MUC1, byadministering to the patient a therapeutically effective amount of acomposition comprising a structure: Ak-Aa-Cy wherein Ak is an alkylgroup, Cy comprises a cyclic structure, Aa consists of a natural aminoacid, and the patient is not otherwise indicated for treatment with thecomposition.
 38. A method, comprising: treating a human patientsusceptible to or exhibiting symptoms of a cancer characterized byaberrant expression of MUC1, by administering to the patient atherapeutically effective amount of a composition comprising astructure: Cy¹-Aa-Cy² wherein Cy¹ and Cy² each independently comprise acyclic structure, Aa consists of a natural amino acid, and the patientis not otherwise indicated for treatment with the composition.
 39. Acomposition, comprising a structure:

wherein R¹¹, R¹², R¹³, R¹⁴, R¹⁵, R³⁰ and R³¹ each independently compriseat least one atom, and G¹, G², G³, G⁴, G⁵, and G⁶ each independentlycomprise at least one atom able to form at least three covalent bonds;in combination with a pharmaceutically acceptable carrier.
 40. A method,comprising: treating a human patient susceptible to or exhibitingsymptoms of a cancer characterized by aberrant expression of MUC1, byadministering to the patient a therapeutically effective amount of acomposition comprising:

wherein Cy comprises a cyclic structure having at least seven members,R³⁰, R³¹, and R³² each comprise at least one atom, and the patient isnot otherwise indicated for treatment with the composition.
 41. Acomposition, comprising a structure:

wherein R³⁰, R⁴⁰, R⁴¹, R⁴², R⁴³, R⁴⁴, R⁵⁰, R⁵¹, R⁵², R⁵³, and R⁵⁴ eachindependently comprise at least one atom; in combination with apharmaceutically acceptable carrier.
 42. A composition, comprising astructure:

wherein R¹¹, R¹², R¹³, and R⁴⁰ each independently comprise at least oneatom, G¹, G², G³, G⁴, G⁵, G⁶, G⁷, G⁸, and G⁹ each independently compriseat least one atom able to form at least three covalent bonds, and Ecomprises at least 2 cyclic groups; in combination with apharmaceutically acceptable carrier.
 43. A composition, comprising astructure:

wherein R⁶⁰, R⁶¹, R⁷⁰, R⁷¹, R⁷², R⁷³, and R⁷⁴ each independentlycomprises at least one atom, G¹, G², G³, G⁴, G⁵, G⁶, and G⁷ eachindependently comprise at least one atom able to form at least threecovalent bonds, and J comprises a chemical bond or at least one atom; incombination with a pharmaceutically acceptable carrier.